Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[N:17]([CH:18]=2)[CH:16]=[C:15]([C:19]([NH2:21])=[O:20])[CH:14]=[CH:13]3)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:24]I>CN(C=O)C.C1COCC1>[CH3:24][NH:21][C:19]([C:15]1[CH:14]=[CH:13][C:12]2[N:17]([CH:18]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH:11]=2)[CH:16]=1)=[O:20]
Reactant: NC(=O)c1ccc2cc(-c3cccc([N+](=O)[O-])c3)cn2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc(-c3cccc([N+](=O)[O-])c3)cn2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 23.8 %

Procedure:
To a cooled solution of 2-(3-nitrophenyl)indolizine-6-carboxamide (0.4 g, 1.42 mmol) in DMF/THF (20/10 ml) was added NaH (60% in mineral oil, 58 mg, 1.45 mmol). The resulting mixture was stirred under Ar at 0° C. for 5 min, and then MeI (0.13 mL, 2.08 mmol) was added. The reaction mixture was stirred under Ar at 0° C. and warmed gradually to room temperature and stirred at room temperature overnight. It was concentrated in vacuo. The residue was recrystallized from CH2Cl2/acetone/EtOAc to give a white solid (0.1 g, 24%). 1H NMR (CDCl3, 400 MHz) δ: 8.78 (s, 1H), 8.48 (t, J=2.0 Hz, 1H), 8.42 (br s, 1H), 8.30 (d, J=1.6 Hz, 1H), 8.18 (d, J=7.6 Hz, 1H), 8.09 (dd, J=8.0, 1.6 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.45 (d, J=9.2 Hz, 1H), 7.13 (dd, J=9.6, 1.6 Hz, 1H), 6.99 (s, 1H), 2.77 (d, J=4.4 Hz, 3H). MS: m/z=296 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1cc(Cl)c2ccccc2n1
Product: Cc1cc(NCc2ccc(F)cc2)c2ccccc2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methylquinoline and 4-fluorobenzylamine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11].Cl>C(OCCO)C.[Cl-].[Na+].O.O>[CH3:8][C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=2)[CH:5]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: O
Product: Cc1cc(Nc2cccc([N+](=O)[O-])c2)nc(N)n1
Temperature: 25 °C

Procedure:
To a suspension of 2-amino-4-chloro-6-methyl-pyrimidine (A8) [10.04 g, 69.93 mmol] and 3-nitroaniline 99.95 g, 72.02 mmol) in 2-ethoxyethanol (300 mL) was added c.HCl (30 mL), and the resulting solution was refluxed for ˜16 h. After this time, the reaction mixture was allowed to cool to room temperature, and then diluted with brine and H2O. The resulting suspension was filtered through a Celite pad, and the solid material thus collected re-dissolved in MeOH, and filtered through a pad of Celite. Solvent was removed under reduced pressure to give diamine E1 as an amorphous beige solid, which was used without further purification: 1H NMR (400 MHz, DMSO): δ 12.97 (br s, 1H, pyrimidinyl-N+—H), 11.03 (s, 1H, ArNHAr), 8.52 (s, 1H, ArH), 8.31 (d, J=7.83 Hz, 1H, ArH), 7.97 (ddd, J=8.20, 2.19, 0.72 Hz, 1H, ArH), 7.83 (v br s, 2H, ArNH2), 7.66 (t, J=8.21 Hz, 1H, ArH), 6.25 (s, 1H, ArH), 2.31 (s, 3H, ArCH3); LCMS (APCl+): 246 (100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][C:14]([Cl:20])=[CH:15][CH:16]=3)[N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)=[O:22]>>[Cl:20][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10](/[CH:9]=[CH:8]/[C:4]3[CH:3]=[C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH:21]=[O:22])[CH:7]=[CH:6][CH:5]=3)=[N:11]2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: Clc1ccc2ccc(/C=C/c3cccc(Br)c3)nc2c1
Product: O=Cc1ccccc1-c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1

Procedure:
Prepared as described in Example 1 (step 1) from (E)-2-[2-(3-bromophenyl)vinyl]-7-chloroquinoline (prepared as described Example 8 (step 6), from 3-bromobenzaldehyde) and 2-formyl benzeneboronic acid (1.5 eq.). Title compound was purified by swish (Hex: CH2Cl2). 1H NMR (CDCl3) δ 7.3-7.6 (6H, m), 7.6-7.8 (6H, m), 8.0-8.1 (3H, m), 10.03 (1H, d).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=O)[NH:14][C:10]=2[C:9]([CH3:17])=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:13]1[N:12]([CH3:16])[C:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[C:9]([CH3:17])[C:10]=2[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(CC)c1ccc(C)c2[nH]c(=O)n(C)c12
Product: CCC(CC)c1ccc(C)c2nc(Cl)n(C)c12
Temperature: 110 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 7-(1-ethylpropyl)-1,4-dimethyl-1,3-dihydro-2H-benzimidazol-2-one (105 mg, 0.452 mmol) in phosphorous oxychloride (1.23 mL) was stirred at 110° C. for 3 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=10:1-1:1) and crystallized from ethyl acetate/n-hexane to afford the title compound as colorless crystals (100 mg, 88%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])(=O)C.[K+].C(O)CCC>CCOCC.O>[F:10][C:11]1[C:16]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: CNc1cc(Cl)ncn1
Reactant: OB(O)c1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCCCO
Product: CNc1cc(-c2cccnc2F)ncn1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
To an RBF, under a reflux condenser, was added 6-chloro-N-methylpyrimidin-4-amine (5.0 g, 35 mmol), 2-fluoropyridin-3-ylboronic acid (7.4 g, 52 mmol), potassium acetate (10 g, 104 mmol), 1-butanol (100 mL) and DI water (20 mL). The mixture was purged with Ar (vacuum/purge three times to remove oxygen), then PdCl2(P-t-Bu2Ph)2 (0.26 g, 0.42 mmol) was added. The reaction mixture was stirred in a 100° C. oil bath for 17 h. The reaction mixture was allowed to cool to room temperature and diluted with Et2O (500 mL). The mixture was washed with water (3×200 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo to ˜100 mL bright yellow butanol solution. The solution was azeotroped with hexane (3×500 mL). Upon the third azeotrope (volume ˜90 mL) a white precipitate was observed. The suspended solid was collected by solution filtration and vacuum-dried to afford 2.48 g as a white solid. The filtrate was diluted with Et2O (300 mL) and extracted with 1 N aq HCl (2×150 mL). The aqueous extract was basified with 5 N NaOH and extracted with Et2O (2×150 mL). The organic extract was washed with saturated NaCl (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 2.48 g as an off-white solid. Total yield of title compound: 6-(2-fluoropyridin-3-yl)-N-methylpyrimidin-4-amine (4.95 g, 70%). MS (M+H)+ 205.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][OH:8])[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[C:4]([C:9]([F:10])([F:11])[F:12])=[N:3]1
Reactant: Cn1cc(CO)c(C(F)(F)F)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cn1cc(C=O)c(C(F)(F)F)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Dissolve (1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol (1.41 g, 7.83 mmol) in DCM (25 mL) and dimethylsulfoxide (2.22 mL, 31.3 mmol) and cool to −78° C. Add oxalyl chloride (1.91 mL, 21.9 mmol) dropwise over 15 min. and stir at −78° C. for an additional 1 hr. Add triethylamine (6.55 mL, 47.0 mmol) dropwise and stir another 1 hr. Quench with water (20 mL) and dilute with DCM (50 mL) and warm to room temperature for 1 hr. Separate the organic layer; dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 80:20 hexanes:ethyl acetate), to give the title preparation (0.98 g, 71%). 1H-NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.97 (s, 1H), 3.99 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].[OH-].[K+].Br[CH2:14][CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(Cl)Cl>CC(C)=O>[Si:18]([O:17][CH2:16][CH2:15][CH2:14][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCn1c(N)nc2ccccc21
Reaction time: 1 h
Yield: 17.3 %

Procedure:
1H-Benzoimidazol-2-ylamine (1 g, 7.5 mmol) was dissolved in acetone (30 mL) and powdered potassium hydroxide (2.12 g, 37.5 mmol) was added. The reaction was allowed to stir for several minutes at room temperature before (3-bromopropoxy)(tert-butyl)dimethylsilane (1.75 mL, 7.5 mmol) was added. After 1 hour, methylene chloride was added and the mixture was washed with water, brine and dried over magnesium sulfate. Upon concentration the crude product was dissolved in methylene chloride and purified by combiflash chromatography, methylene chloride to methylene chloride 6% MeOH gradient, to give 1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-benzo[d]imidazol-2-amine (0.400 g, 1.3 mmol).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[CH2:44][CH2:43][N:35]3[C:36]4[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[CH:42]=[C:34]3[C:33]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:29]=[C:22]3[CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.O.[OH-].[Li+]>CC(O)C.O1CCCC1>[CH2:27]([N:24]1[CH2:25][CH2:26][N:21]2[N:20]=[C:19]([NH:18][C:16]3[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:32]5[CH2:44][CH2:43][N:35]6[C:36]7[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=7[CH:42]=[C:34]6[C:33]5=[O:45])[C:6]=4[CH2:5][OH:4])[CH:17]=3)[CH:29]=[C:22]2[CH2:23]1)[CH3:28]
Reactant: CCN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4COC(C)=O)cn(C)c3=O)cc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CCN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
To a solution of 177a (300 mg, 0.49 mmol) in propan-2-ol (4 mL), tetrahydrofuran (4 mL), and water (1 mL) was added lithium hydroxide (35 mg, 1.47 mmol). The mixture was stirred at room temperature for 0.5 h. It was evaporated and the residue was purified by reverse-phase prep-HPLC to afford 177 (79 mg, 28%) as a white solid. MS-ESI: [M+H]+ 569. 1H NMR (500 MHz, CDCl3) δ 8.46 (d, J=5.5 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.39 (s, 1H), 7.33 (d, J=5.5 Hz, 1H), 6.88 (s, 1H), 5.69 (s, 1H), 4.99-4.97 (m, 1H), 4.61-4.60 (m, 1H), 4.48-4.46 (m, 1H), 4.33-4.31 (m, 1H), 4.14-4.06 (m, 4H), 3.87-3.85 (m, 1H), 3.69 (s, 3H), 3.62 (d, J=5.5 Hz, 2H), 2.91 (d, J=5.0 Hz, 2H), 2.63-2.55 (m, 6H), 1.91-1.87 (m, 2H), 1.79-1.78 (m, 2H), 1.17 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11]C[N:9]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]2=[O:19])=[C:4]([Cl:22])[CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:22][C:4]1[CH:3]=[C:2]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:5]=1[CH2:6][CH:7]1[CH2:12][CH2:11][N:9]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C:8]1=[O:19]
Reactant: Nc1ccccc1
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCCN1C1CCCCC1
Product: O=C1C(Cc2ccc(Nc3ccccc3)cc2Cl)CCN1C1CCCCC1
Yield: 61 %

Procedure:
Prepare essentially as described in Example 228, using 3-(4-bromo-2-chloro-benzyl)-1-cyclohexyl-piperidin-2-one and aniline. Evaporate the crude reaction mixture and purify by chromatography on silica gel to give the title compound (127 mg, 61%). MS (ES+) m/z=383 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:30][CH:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].C([BH3-])#N.[Na+].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(O)(=O)C>CO.O>[F:1][C:2]1[C:3]([NH:30][CH:31]2[CH2:32][CH2:33][CH:34]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH2:35][CH2:36]2)=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: C1COCCN1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cc(F)c(NC4CCC(=O)CC4)c(C(=O)N(C)C)c3)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(F)c(NC4CCC(N5CCOCC5)CC4)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-2-(4-oxo-cyclohexylamino)-benzamide (91 mg, 0.14 mmol), sodium cyanoborohydride (17.5 mg, 0.28 mmol), and morpholine (37 μL, 0.41 mmol) were dissolved in 1.7 mL methanol, containing 5% v/v of glacial acetic acid and 2% v/v of water. The reaction was stirred for 2 hrs at ambient temperature and quenched with a saturated sodium bicarbonate solution. The mixture was concentrated, suspended in a minimal amount of water and loaded onto a 5 g C18 functionalized silica gel cartridge. The cartridge was washed with 1 N aqueous potassium hydrogensulfate and water. Elution with acetonitrile and evaporation of the solvent afforded a brown oil which was purified by reverse-phase HPLC to afford 10.4 mg (0.014 mmol, 10%) of both diastereoisomers of 3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-2-(4-morpholin-4-yl-cyclohexylamino)-benzamide as a white powder. More polar diastereoisomer (4.5 mg) 1H NMR (500 MHz, DMSO-d6) δ13.75 (bs, 1H), 8.81 (d, J=2 Hz, 1H), 8.27 (d, J=2 Hz, 1H), 8.16 (s, 1H), 7.62 (dd, J=7.5 Hz, J2=1.5 Hz, 1H), 7.58 (dd, J=13.5 Hz, J2=2 Hz, 1H), 7.45 (ddd, J=8 Hz, J2=7 Hz, J3=1.5 Hz, 1H), 7.30 (d, J=2 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (td, J=7.5 Hz, J2=1 Hz, 1H), 4.56 (d, J=9 Hz, 1H), 3.82 (s, 3H), 3.53 (t, J=4.5 Hz, 4H), 3.11 (m, 1H), 2.99 (bs, 3H), 2.90 (s, 3H), 2.43 (t, J=4.5 Hz, 4H), 2.14 (m, 1H), 1.88 (m, 2H), 1.82 (m, 2H), 1.17 (m, 4H). MS: m/z 573.4 (M+H+). Less polar diastereoisomer (5.9 mg) 1H NMR (500 MHz, DMSO-d6) δ13.77 (bs, 1H), 8.82 (s, 1H), 8.30 (s, 1H), 7.61 (m, 2H), 7.45 (t, J=8 Hz, 1H), 7.34 (m, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (t, J=8 Hz, H), 4.87 (d, J=9 Hz, 1H), 3.82 (s, 3H), 3.56 (m, 5H), 2.96 (m, 6H), 2.41 (m, 4H), 2.14 (m, 1H), 1.65 (m, 2H), 1.51 (m, 2H), 1.48 (m, 4H). MS: m/z 573.3 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=O)(C)(C)C.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1ccccc1Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccccc1OC1CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
1-tert-Butyloxycarbonyl-3-hydroxypyrrolidine (1 g), 2-bromophenol (710 mg) and triphenylphosphine (1.29 g) were dissolved in tetrahydrofuran (15 ml) and the mixture cooled in an ice bath before dropwise addition of diisopropyl azodicarboxylate (0.96 ml). The mixture was allowed to warm to room temperature over 3 h, concentrated in vacuo, partitioned between ether (50 ml) and water (50 ml) and the aqueous phase was extracted further with ether (50 ml). The combined organic phases were washed with water (2×25 ml), brine (2×25 ml), dried (MgSO4) and concentrated in vacuo. The product was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (5 ml) was added and the reaction stirred for 1 h. The mixture was concentrated in vacuo and the residue was purified by cation exchange chromatography eluting with ammonia/methanol/dichloromethane mixtures. This gave the title compound as a pale orange oil (437 mg).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8](F)[C:7]([F:12])=[C:4]([C:5]#[N:6])[C:3]=1[C:13]#[N:14].[CH3:15][CH:16]([CH:18]([O:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26]=1[OH:37])=[O:24])[CH:19]([CH3:21])[CH3:20])[CH3:17].[F-].[K+]>C(#N)C>[F:12][C:7]1[C:8]([O:37][C:26]2[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]([O:22][CH:18]([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:15])[CH3:17])=[O:24])=[C:9]([F:10])[C:2]([F:1])=[C:3]([C:13]#[N:14])[C:4]=1[C:5]#[N:6]
Reactant: CC(C)C(OC(=O)c1cccc(-c2ccccc2)c1O)C(C)C
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)C(OC(=O)c1cccc(-c2ccccc2)c1Oc1c(F)c(F)c(C#N)c(C#N)c1F)C(C)C
Yield: 93.4 %

Procedure:
In a four-neck flask having an inner volume of 100 ml, 3.00 g (15 m.mols) of 3,4,5,6-tetrafluorophthalonitrile, 4.69 g (15 m.mols) of 2-(2,4-dimethyl-3-pentyloxy)carbonyl-6-phenylphenol, 2.62 g (45 m.mols) of potassium fluoride, and 50 ml of acetonitrile were placed and left reacting under reflux for six hours. After the reaction, the reaction mass was filtered and then distilled to expel the solvent by evaporation and obtain 6.90 g (14 m.mols) of 3,5,6-trifluoro-4-(2-(2,4-dimethyl-3-pentyloxy)carbonyl-6-phenylphenoxy)phthalonitrile as the product aimed at.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25]Cl)=[N:23][N:24]=2)[CH:3]=1.[CH3:27][C@H:28]1[O:33][C@@H:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:30]3[CH2:29][C@H:28]([CH3:27])[O:33][C@H:32]([CH3:34])[CH2:31]3)=[N:23][N:24]=2)[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2nnc(-c3cc(Br)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@H](C)O1
Temperature: 50 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To a solution of 6-bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-(phenylsulfonyl)-1H-indazole (1.7 g, 3.75 mmol) in dichloromethane (50 ml) was added (2R,6S)-2,6-dimethylmorpholine (0.863 g, 7.49 mmol) and the mixture stirred at 50° C. for 18 hr. The crude product was purified by silica (100 g) cartridge on Flashmaster II using a gradient of dichloromethane and methanol to give the title compound as a pale yellow solid (1.79 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[CH:11][CH:10]=[C:9]([C@@H:13]([OH:24])[C@H:14]3[N:19]4[CH2:20][C@H:21]([CH:22]=[CH2:23])[C@@H:16]([CH2:17][CH2:18]4)[CH2:15]3)[C:7]=2[CH:8]=1.[C:25]([OH:42])(=[O:41])[C:26]1[C:27](=[CH:31][C:32](=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])[C:33]([OH:35])=[O:34])[C:28]([OH:30])=[O:29].O.C(O)C>C(O)CC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[CH:11][CH:10]=[C:9]([C@@H:13]([OH:24])[C@H:14]3[N:19]4[CH2:20][C@H:21]([CH:22]=[CH2:23])[C@@H:16]([CH2:17][CH2:18]4)[CH2:15]3)[C:7]=2[CH:8]=1.[C:33]([O-:35])(=[O:34])[C:32]1[C:36](=[CH:40][C:26](=[C:27]([CH:31]=1)[C:28]([O-:30])=[O:29])[C:25]([O-:42])=[O:41])[C:37]([O-:39])=[O:38]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1C(=O)O
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: O
Solvent: CCO
Solvent: CCCO
Product: O=C([O-])c1cc(C(=O)[O-])c(C(=O)[O-])cc1C(=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Four grams of quinine, 2.6 g. pyromellitic acid and 50.0 g. H2O were combined with stirring and heated to 80° C. 310.0 cc ethanol and 5.0 cc n-propanol were added and the mixture held at 70°-80° C. for about 30 minutes. The reaction product was filtered hot and 3.62 g. of dry cake, M.P. 220° C. (not sharp) was obtained.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:21][CH:9]3[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][C:8]3([CH3:22])[C:6]=2[CH:7]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[C:38]1([SH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>[Cu]I>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][C:8]2([CH3:22])[C:6]3[CH:7]=[C:2]([S:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:3]=[CH:4][C:5]=3[O:21][CH:9]2[CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3cc(I)ccc3OC2C1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: OCCO
Product: CC(C)(C)OC(=O)N1CCC2(C)c3cc(Sc4ccccc4)ccc3OC2C1
Temperature: 120 °C

Procedure:
Into a sealed tube was added tert-butyl 6-iodo-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P24 (0.491 g, 1.18 mmol), sodium tert-butoxide (341 mg, 3.55 mmol), copper (I) iodide (20 mg, 0.08 mmol), 1,2-ethanediol (132 μL, 2.38 mmol), N,N-dimethylformamide (17 mL, 210 mmol), and benzenethiol (123 μL, 1.19 mmol). The reaction was heated at 120° C. overnight. The reaction was concentrated and partitioned between DCM and water. The DCM layer was washed with brine, dried, filtered and concentrated under vacuum. The crude product was dissolved in DCM and purified on a 12 g silica gel column eluting with hexanes to 2:1 hexanes:ethyl acetate to give the product which was taken directly into the next step.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[C:16]([N+:24]([O-:26])=[O:25])[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:13]1[CH2:14][CH2:15][N:11]([CH3:10])[C:12]1=[C:16]([N+:24]([O-:26])=[O:25])[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCNC1=C(Sc1ccccc1)[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccccc2)C1=C(Sc1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.71 g of benzoyl chloride was added to 1.26 g of 1B and 0.63 g of triethylamine in 25 ml of methylene chloride at 0°-20°. After stirring overnight at room temperature, the solvent was stripped. The solid residue was triturated with ice-cold methanol and then filtered to give 2, as a yellow solid, m.p.: 175°-178°.