Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:10]([NH2:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[C:1]1([C:7]2([CH2:10][NH2:12])[CH2:8][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(c2ccccc2)CC1
Temperature: 65 °C
Yield: 48.7 %

Procedure:
A solution of 1-phenylcyclopropanecarboxamide (0.450 g, 2.79 mmol) in tetrahydrofuran (5 mL) was slowly added to a suspension of LAH (0.117 g, 3.07 mmol) in tetrahydrofuran (5 mL) at 23° C. over 2 minutes. The reaction was then heated to 65° C. for 6 hours. The reaction was quenched with the Rochelle salt (1N in water, 10 mL) and extracted with ethyl acetate (3×). The combined organic layers were then dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude title material (0.200 g, 49%) as an oil which was used as such in the next reaction. An aliquot was purified on preparative HPLC (ammonium acetate/water/acetonitrile). 1H NMR (400 MHz, CDCl3, acetic acid salt) δ: 0.83-0.94 (4H, m), 1.98 (3H, s), 2.90 (2H, s), 4.98 (3H, br s), 7.23-7.37 (5H, m).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][NH:21]4)=[CH:15][N:16]=[C:11]2[N:10]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45]C([O-])(C)C.[K+].IC>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][N:21]4[CH3:45])=[CH:15][N:16]=[C:11]2[N:10]([C:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3cccc4[nH]ncc34)nc12
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1ncc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
To a solution of N-tert-butyl-2-(1H-indazol-4-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (375 mg, 0.65 mmol) in dry THF (20 mL) was added potassium 2-methylpropan-2-olate (109 mg, 0.975 mmol) at 0° C. After stirring for 30 minutes, iodomethane (138 mg, 0.975 mmol) was added at 0° C. Then it was warmed to room temperature and stirred for 1 hour. Reaction mixture was quenched by the addition of water (2 mL), extracted with ethyl acetate (100 mL), then organic phase washed with water (3×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with EtOAc: petroleum ether=1:3) to afford N-tert-butyl-2-(1-methyl-1H-indazol-4-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (154 mg, 40%) as a white solid. LCMS: (M+H)+=591; 1H NMR (300 MHz, CDCl3): δ 8.54 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 7.53-7.47 (m, 3H), 7.32-7.27 (m, 9H), 7.24-7.19 (m, 6H), 4.14 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[C:10]1(OB(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O.C(OCC)(=O)C>[C:10]1([C:2]2[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1cccc(Cl)n1
Reactant: OB(O)Oc1ccccc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(-c2ccccc2)n1
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
6-Chloro-2-pyridinecarbonitrile (0.80 g, 5.7 mmol) and phenylboric acid (1.05 g, 8.6 mmol) were dissolved in toluene (60 ml)-ethanol (15 ml), and potassium carbonate (2.00 g, 14.4 mmol) and water (15 ml) were added thereto. The mixture was deairated under reduced pressure for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.33 g, 0.29 mmol) was added to the reaction mixture under argon atmosphere, and the mixture was refluxed for 16 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (0.90 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[S:17][C:15]=2[N:16]=1
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccc(F)cc1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:34]12[O:41][CH:38]([CH2:39][CH2:40]1)[CH2:37][C:36](=O)[CH2:35]2>C1COCC1>[CH3:12][O:13][CH:14]=[C:36]1[CH2:37][CH:38]2[O:41][CH:34]([CH2:40][CH2:39]2)[CH2:35]1
Reactant: O=C1CC2CCC(C1)O2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC=C1CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium bis(trimethylsilyl)amide 1M in THF (24.48 ml, 24.48 mmol) was added drop wise to a suspension of (methoxymethyl)triphenylphosphonium chloride (8.39 g, 24.48 mmol) in THF (98 ml) at −40° C. Stirring was continued for 0.5 h at −40° C. and then the solution of 8-oxa-bicyclo[3.2.1]octan-3-one [CAS #77745-32-5] (1.93 g, 15.3 mmol) in THF (20 ml) was added at −40° C. The suspension was allowed to warm to RT and stirring was continued for 6 h. The reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography (eluting with a gradient of heptane-EtOAc 97:3 to 0:100) yielding the title compound as a slightly yellow oil (1.71 g, 11.09 mmol, 72%): 1H-NMR (400 MHz, CDCl3): δ 1.58-2.43 (m, 8H), 3.54 (s, 3H), 4.41 (m, 2H), 5.85 (s, 1H)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].B(OC(C)C)(OC(C)C)OC(C)C.C([N-]C(C)C)(C)C.[Li+].Br[C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(COC)OC.O.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:37]([C:34]1[CH:35]=[CH:36][C:31]([C:6]2[N:2]([CH3:1])[C:3]([C:7]#[N:8])=[CH:4][CH:5]=2)=[CH:32][CH:33]=1)(=[O:39])[CH3:38]
Reactant: Cn1cccc1C#N
Reactant: CC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(C#N)n2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a stirred solution of 1-methyl-2-cyanopyrrole (1.6 g, 15 mmol) and triisopropyl borate (7.0 mL, 30 mmol) in tetrahydrofuran (THF—45 mL) at 0° C. was added lithium diisopropylamide (LDA—2.0 M in heptane/THF/ethylbenzene, 13.3 mL, 26.6 mmol) in a dropwise fashion over 45 minutes. The resulting solution was stirred at 0° C. for 1 hour. To the solution was added 1-(4-bromophenyl)-ethanone (1.0 g, 5 mmol) dissolved in glyme (45 mL), sodium carbonate (1.59 g, 15 mmol) dissolved in water (9 mL), and tetrakis(triphenylphosphine)palladium (0) (0.28 g, 0.25 mmol). The resulting solution was heated to reflux for 1.5 hours. The solution was cooled to room temperature and partitioned between a saturated aqueous ammonium chloride solution (50 mL) and ethyl acetate (80 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (20% ethyl acetate in hexane) and triturated with ether to give 5-(4-acetylphenyl)-1-methyl-1H-pyrrole-2-carbonitrile as a yellow solid (0.62 g, 55%). MS (ES) m/z 225.1; HRMS: calcd for C14H12N2O+H+, 225.1022; found (ESI, [M+H]+), 225.1039.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[C:24]=2I)=[CH:8][CH:7]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[C:24]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)c(I)n2n1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)c(-c3ccccc3)n2n1

Procedure:
2-[4-(2-Methoxyethoxy)phenyl]-3-iodo-6-propoxyimidazo[1,2-b]pyridazine (100 mg, 0.22 mmol) was dissolved with stirring in 1,2-dimethoxyethane (2.5 mL) under an atmosphere of nitrogen. Phenylboronic acid (30 mg, 0.24 mmol) was added followed by tetrakis(triphenylphosphine)-palladium(0) (20 mg). A solution of sodium hydroxide (18 mg, 0.44 mmol) in water (1 mL) was added. The resulting mixture was heated at 70° for 1 hour then cooled and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organics dried and evaporated. The cream coloured solid residue was radially chromatographed on silica gel. Elution with 0-3% methanol in dichloromethane provided Compound 97 (74 mg) as a white solid. 1H n.m.r. (CDCl3) δ 1.00, t, J=7.3 Hz, 3H; 1.74-1.86, m, 2H; 3.45, s, 3H; 3.75, t, J=4.3 Hz, 2H; 4.13, t, J=4.3 Hz, 2H; 4.18, t, J=6.3 Hz, 2H; 6.70, d, J=9.5 Hz, 1H; 6.88, d, J=8.4 Hz, 2H; 7.35-7.47, m, 3H; 7.57, d, J=8.3 Hz 2H; 7.62, d, J=6.8 Hz, 2H; 7.82, d, J=9.3 Hz, 1H. Mass spectrum (APCI+) m/z 404 (M+H, 100%).
Reaction SMILES: C([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[Cl:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25]([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[Cl:23])[CH2:10][CH2:9]1)=[O:26])[CH3:29]
Reactant: Clc1c2c(nc3ccccc13)CCN(Cc1ccccc1)CC2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCc2nc3ccccc3c(Cl)c2CC1
Yield: 97 %

Procedure:
11-Chloro-1,2,4,5-tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared analogous to Example 98 from 3-benzyl-11-chloro-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline and ethyl chloroformate.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@H:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].[OH-].[Na+].Cl>CO>[N:11]1([C:9]([NH:8][C@H:7]([C:6]([NH:5][C@@H:4]([C:3]([OH:33])=[O:2])[CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)N1CCCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
The compound obtained in (3) (1.29 g) was dissolved in methanol (5.0 ml) and 1N NaOH (3.1 ml) was added at 0°~5° C. Then the reaction mixture was stirred at room temperature for 2 h. 1N HCl (3.1 ml) was added to the mixture and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed with 1N HCl and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from methanol (5 ml)/ethyl acetate (30 ml)/hexane (60 ml) to give the product (0.97 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:6]([N+:25]([O-])=O)[CH:5]=1>[Pd].C(O)C>[NH2:25][C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=[CH:8][C:7]=1[CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19]
Reactant: COCc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COCc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(N)c1
Reaction time: 16 h
Yield: 96 %

Procedure:
A mixture of bis(1,1-dimethylethyl) {4-[(methyloxy)methyl]-2-nitrophenyl}propanedioate (D123) (1.30 g, 3.41 mmol) and palladium on carbon (0.181 g, 0.170 mmol) in ethanol (30 mL) was stirred under hydrogen at atmospheric pressure for 16 hr. The catalyst was removed by filtration through celite and the filtrate concentrated to dryness under vacuum to afford the crude title compound as a thick yellow oil 1.15 g, 96%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[N:18]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2>>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[N:18]1)[N:5]=[CH:4][CH:3]=[C:2]2[NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2)#[N:13]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCn1ccnn1
Product: N#Cc1cc2c(Nc3ccc4[nH]ccc4c3)ccnc2cc1OCCn1ccnn1
Yield: 93.6 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6-cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinoline (60 mg, 0.2 mmol) was reacted with 5-aminoindole (32 mg, 0.25 mmol) to give 6-cyano-4-(indol-5-ylamino)-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinoline (74 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][C:53]([O:56][C:57]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH:64]([O:70][N+:71]([O-:73])=[O:72])[CH2:65][O:66][N+:67]([O-:69])=[O:68])=[O:58])([CH3:55])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]>ClCCl.CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][C:53]([O:56][C:57]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH:64]([O:70][N+:71]([O-:73])=[O:72])[CH2:65][O:66][N+:67]([O-:69])=[O:68])=[O:58])([CH3:55])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A dichloromethane/methanol (3.5 mL, 1:7) solution of 1-[({[5,6-bis(nitrooxy)hexyl]oxy}carbonyl)oxy]-1-methylethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (0.190 g, 0.192 mmol) was heated in a microwave apparatus (90° C., 20 minutes). Then the solution was concentrated and the residue was purified by flash chromatography (Biotage SP1, 25+M column, dichloromethane/methanol 98/2), affording the title compound. 1H NMR (300 MHz, CDCl3) δ 8.04-8.01 (m, 1H), 7.63-7.61 (m, 2H), 7.52 (dd, 1H), 7.32-7.28 (m, 1H), 6.91 (t, 1H), 6.81 (d, 3H), 6.68 (d, 2H), 5.62 (s, 2H), 5.25-5.23 (m, 1H), 4.72 (dd, 1H), 4.28-4.26 (m, 2H), 4.05 (t, 2H), 1.78-1.52 (m, 10H), 1.49-1.42 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].[Cl:14][C:15]1[C:16]([F:37])=[C:17]([CH:26]2[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]2)[C:18]([O:24][CH3:25])=[C:19]([CH:21](Cl)[CH3:22])[CH:20]=1>CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:21]([C:19]3[C:18]([O:24][CH3:25])=[C:17]([CH:26]4[CH2:27][N:28]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:29]4)[C:16]([F:37])=[C:15]([Cl:14])[CH:20]=3)[CH3:22])[N:3]=[C:2]([CH3:1])[C:10]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (7.9 mg, 0.053 mmol) in N,N-dimethylformamide (0.6 mL) was added sodium hydride (60%, 2.5 mg, 0.11 mmol) at 0° C. and the mixture was stirred at room temperature for 10 minutes. To the mixture was added a solution of tert-butyl 3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate (20 mg, 0.053 mmol) in N,N-dimethylformamide (0.3 mL). The reaction mixture was stirred at 35° C. overnight, then quenched with water, extracted with ether. The combined organic layers were dried over MgSO4 and concentrated to afford the desired product which was used in next step directly. LCMS calculated for C23H29ClFN6O3 (M+H)+: m/z=491.2; Found: 491.1.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]#[CH:17].[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]#[C:17][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:25]
Reactant: O=Cc1ccccc1
Reactant: C#Cc1ccco1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: OC(C#Cc1ccco1)c1ccccc1
Temperature: 25 °C

Procedure:
Place lithium hexamethyldisilazane (3 mL of a 1M solution in tetrahydrofuran, 3 mmol) under argon atmosphere and cool to 0° C. Add 2-furanylacetylene (276 mg, 3 mmol) in tetrahydrofuran (20 mL) and stir at 0° C. until anion formation is complete. Add a solution of benzaldehyde (297 mg, 2.8 mmol) in tetrahydrofuran, remove the ice bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgSO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[C:7](N1CCCC1)[CH2:6][CH2:5]2.C([O-])(=[O:20])C.[Na+].C(O)(=O)C.O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH3:12])[C:7](=[O:20])[CH2:6][CH2:5]2
Reactant: CC(=O)[O-]
Reactant: CC1=C(N2CCCC2)CCc2cc(F)ccc21
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1C(=O)CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To the 6-fluoro 1-methyl-2-pyrrolidinyl-3,4-dihydronaphthalene afforded above in Step B in 1700 ml of ethyl acetate was added sodium acetate (10.2 g; 124.4 mmol), acetic acid (10.2 ml; 178.2 mmol) and 102 ml of water. The reaction mixture was stirred at room temperature for 4 hours. The layers were separated and the organic layer was washed with brine, 5% NaHCO3, and brine. The organic layer was dried over MgSO4 and was concentrated to afford 7.9 g of the subtitle compound as a dark orange-red oil (60% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/OCC)[CH:7]=1.O.Cl.[CH3:19][NH:20][CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N:20]([CH3:21])[CH3:19])[CH:5]=[N:4][C:3]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CCO/C=C/c1cnc(C(F)(F)F)c(Br)c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)CCc1cnc(C(F)(F)F)c(Br)c1
Temperature: 105 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
To a solution of 3-bromo-5-[(E)-2-ethoxyvinyl]-2-(trifluoromethyl)-pyridine (0.35 g, 1.18 mmol) in AcOH (9 mL) was added water (3 mL). The resulting mixture was allowed to stir overnight at 105° C. The mixture was allowed to cool to rt. Dimethylamine hydrochloride (0.96 g, 11.8 mmol) and DCM (40 mL) were added. The resulting mixture was allowed to stir for 2 h. Sodium triacetoxyborohydride (0.50 g, 2.36 mmol) was added in portions over 50 min. The resulting mixture was allowed to stir for 3 h and was then concentrated. To the residue was added saturated NaHCO3 (40 mL), and the mixture was extracted with EtOAc (2×30 mL). The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-[5-bromo-6-(trifluoromethyl)pyridin-3-yl]-N,N-dimethylethanamine (0.052 g, 15%) as a solid. LCMS (AA): Rt=1.24 min, m/z=297.0 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].[CH3:11][Si](C=[N+]=[N-])(C)C.CO>CC(OC)(C)C>[I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[O:10][CH3:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Oc1c(I)cc(I)cc1I
Solvent: CO
Solvent: COC(C)(C)C
Product: COc1c(I)cc(I)cc1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 250 mL pressure vessel was added 2,4,6-triiodophenol (5 g, 10.60 mmol) in MTBE (60 ml) to give a yellow solution. The solution was cooled in an ice bath and 2.0M trimethylsilyldiazomethane (7.95 ml, 15.90 mmol) was added at a fast drip followed by dropwise addition of methanol (6 mL) resulting in calm bubbling. The vessel was sealed and stirred at room temperature for 4 h. The reaction solution was partitioned between EtOAc and water and the organic layer was washed with 1M HCl, saturated NaHCO3, and saturated NaCl. The EtOAc was dried (MgSO4), filtered and concentrated to give a tan solid that was used without purification (4.8 g, 94%).
Reaction SMILES: [CH:1]1([CH:6]([NH:8][C:9]2[CH:22]=[CH:21][C:12]([C:13]([CH2:15][C:16]([O:18]CC)=[O:17])=[O:14])=[CH:11][CH:10]=2)[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].S(=O)(=O)(O)O>O.C(O)C>[CH:1]1([CH:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([CH2:15][C:16]([OH:18])=[O:17])=[O:14])=[CH:21][CH:22]=2)[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)c1ccc(NC(C)C2CCCC2)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Nc1ccc(C(=O)CC(=O)O)cc1)C1CCCC1

Procedure:
Two grams of ethyl 4-(1-cyclopentylethylamino)-benzoylacetate is added to a solution of potassium hydroxide in 50 ml. of 1:9 water-ethanol. The reaction of neutralization with sulfuric acid gave a precipitate which is filtered, washed with water, and dried to yield 4-(1-cyclopentylethylamino)benzoylacetic acid.