Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:7][CH2:6][C:5]([N+:13]([O-])=O)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][O:3]1.C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>C(O)(=O)C.[Zn]>[CH2:30]([O:29][C:27]([NH:13][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][O:7][C:2]([CH3:16])([CH3:1])[O:3][CH2:4]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)C1([N+](=O)[O-])COC(C)(C)OC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C1(NC(=O)OCc2ccccc2)COC(C)(C)OC1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a solution of 5.0 g of ethyl 2,2-dimethyl-5-nitro-1,3-dioxane-5-carboxylate in 50 ml of acetic acid was added 7 g of zinc powder in four divided portions at room temperature, followed by stirring at 45° C. for 4 hours. The insoluble materials of the reaction mixture were separated by filtration and washed with chloroform. The filtrate was concentrated under reduced pressure and neutralized by the addition of a saturated aqueous sodium hydrogen carbonate solution. To a mixture formed by adding 100 ml of chloroform thereto were added 2.7 g of sodium hydrogen carbonate and 3.7 ml of benzyl chloroformate at 0° C., followed by stirring at room temperature for 2 hours. The obtained organic layer was dried over anhydrous sodium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6.6 g of ethyl 5-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-1,3-dioxane-5-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:34][C:35]([F:47])([F:46])[C:36]1[CH:45]=[C:44]2[C:39]([CH2:40][CH2:41][CH2:42][NH:43]2)=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=2)[CH:12]=[C:13]([N:43]2[C:44]3[C:39](=[CH:38][CH:37]=[C:36]([C:35]([F:34])([F:46])[F:47])[CH:45]=3)[CH2:40][CH2:41][CH2:42]2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: FC(F)(F)c1ccc2c(c1)NCCC2
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCCc3ccc(C(F)(F)F)cc32)c1
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester and 7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline under the conditions described in Example 24, step (a).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:9][CH:8]([NH:10]S(C(C)(C)C)=O)[CH2:7][CH2:6][CH:5]([C:17]2[N:18]([CH3:25])[N:19]=[CH:20][C:21]=2[N+:22]([O-])=O)[O:4]1)[CH3:2].C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CCN(C(C)C)C(C)C.CCCP(=O)=O.Cl.O1CCOCC1>CO.[OH-].[OH-].[Pd+2]>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:22][C:21]1[CH:20]=[N:19][N:18]([CH3:25])[C:17]=1[C@H:5]1[CH2:6][CH2:7][CH:8]([NH2:10])[CH2:9][C@@H:3]([CH2:1][CH3:2])[O:4]1)=[O:48]
Reactant: CCC1CC(NS(=O)C(C)(C)C)CCC(c2c([N+](=O)[O-])cnn2C)O1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: [Pd+2]
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1CC(N)CC[C@H](c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C)O1
Temperature: 50 °C
Reaction time: 16 h
Yield: 6.1 %

Procedure:
A solution of N-(2-ethyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl)-2-methyl-propane-2-sulfinamide (118 mg, 0.31 mmol) in MeOH (20 mL) was passed through the H-Cube® (full H2, 60° C., flow rate: 1 mL/min, 30 mm 20% Pd(OH)2/C cartridge). The solvent was removed under reduced pressure and the crude residue was re-dissolved in MeOH (1 mL). 5-(tert-Butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (119 mg, 0.33 mmol) was added followed by DIPEA (0.16 mL, 0.95 mmol) and the reaction mixture was heated at 50° C. for 15 min. After cooling to room temperature, propylphosphonic anhydride solution (0.17 mL, 50% wt in EtOAc, 0.34 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL), washed with 1 M aqueous NaOH (3×10 mL), 1 M aqueous HCl (2×10 mL) and brine (10 mL). The organic layer was separated, dried over Na2SO4, concentrated under reduced pressure and purified via silica gel chromatography (0-10% 7 M ammonia in MeOH/DCM) to give an oil as a mixture of isomers. This oil was dissolved in MeOH (2 mL) and HCl in dioxane (4 M, 4.0 mmol, 1 mL) was added. The reaction mixture was stirred at room temperature for 18 hr and the solvents removed under reduced pressure. Purification via chiral preparative HPLC gave 112 as a white solid (9 mg, 5% over three steps). 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 8.15 (s, 1H), 7.34 (tt, J=8.4, 6.1 Hz, 1H), 7.05-6.97 (m, 2H), 6.16 (s, 2H), 4.80 (dd, J=8.2, 3.9 Hz, 1H), 3.77 (s, 3H), 3.71-3.62 (m, 1H), 3.39-3.32 (m, 1H), 2.18-2.09 (m, 1H), 2.08-1.98 (m, 1H), 1.93-1.74 (m, 2H), 1.71-1.57 (m, 3H), 1.46-1.33 (m, 3H), 0.81 (t, J=7.4 Hz, 3H). LCMS (ES+) m/z 477 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:24])=[C:4](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]([O:14][CH2:15][CH3:16])=[C:6]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.N12CCCN=C1CCCCC2.O.[N+:37]([CH3:40])([O-:39])=[O:38]>>[Cl:1][C:2]1[C:3]([F:24])=[C:4]([CH:17]([CH2:40][N+:37]([O-:39])=[O:38])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]([O:14][CH2:15][CH3:16])=[C:6]([C:8]2([CH3:13])[O:9][CH2:10][CH2:11][O:12]2)[CH:7]=1
Reactant: CCOC(=O)/C=C/c1c(F)c(Cl)cc(C2(C)OCCO2)c1OCC
Reactant: C[N+](=O)[O-]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CC(C[N+](=O)[O-])c1c(F)c(Cl)cc(C2(C)OCCO2)c1OCC
Temperature: 60 °C
Reaction time: 15 h

Procedure:
A solution ethyl (2E)-3-[3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl\) phenyl]acrylate (10 g, 28 mmol) (from Step 2) in nitromethane (100 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 mL, 31 mmol) and stirred at 60° C. for 15 h. The reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to a crude orange oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0%-30%) to give the desired product as a mixture of enantiomers (10.4 g, 89%). 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=9.1 Hz, 1H), 4.82 (ddd, J=12.5, 7.6, 1.4 Hz, 1H), 4.68 (dd, J=12.5, 7.2 Hz, 1H), 4.54-4.40 (m, 1H), 4.15-3.90 (m, 6H), 3.89-3.75 (m, 2H), 2.85 (ddd, J=16.0, 8.6, 1.4 Hz, 1H), 2.73 (dd, J=16.1, 6.2 Hz, 1H), 1.70 (s, 3H), 1.47 (t, J=7.0 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H). LCMS for C18H24ClFNO7 (M+H)+: m/z=420.1; Found: 420.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH:15](=O)[CH3:16]>>[CH2:15]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1)[CH3:16]
Reactant: CC=O
Reactant: Nc1ccc(-c2ccc(F)cc2)cn1
Product: CCNc1ccc(-c2ccc(F)cc2)cn1

Procedure:
Compound 70A was reacted with acetaldehyde in a manner analogous to Compound 63C to give the title product. 400 MHz 1H NMR (DMSO-d6) δ ppm 1.1 (t, 3H) 3.2 (q, 2H) 6.6 (m, 2H) 7.2 (m, 2H) 7.5 (m, 3H) 8.2 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7].C1(C)C=CC=CC=1.C(#N)C.[CH2:21]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH2:30][CH3:31])[C:24]=1[C:32](=[O:36])[C:33](Cl)=[O:34])[CH3:22]>O.C(N(CC)CC)C>[CH2:21]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH2:30][CH3:31])[C:24]=1[C:32](=[O:36])[C:33]([N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:34])[CH3:22]
Reactant: CNN=C(C)CS(C)(=O)=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(C)(=O)=O
Temperature: 1 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
To a 100 ml volume four-necked flask, 1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-1) (2.51 g), toluene (anhydrous) (10 ml), acetonitrile (anhydrous) (4.0 ml), and triethylamine (4.0 ml) were added under a nitrogen atmosphere and cooled to about 1° C. To the mixture, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl chloride (6-a) (3.44 g) dissolved in toluene1 (5 ml) was added dropwise over 1 hour, followed by the mixture was stirred at 0° C. for 1.5 hours. Water (30 ml) was added thereto at room temperature, and then the mixture was extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure to give 5.09 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34)-(1)-39).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:15]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:18]([C:29](O)=[O:30])[CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:32]=1.[Na].[N:34]1([CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][NH:42]2)[CH:38]=[CH:37][N:36]=[CH:35]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:15]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C@@H:18]([C:29]([N:42]4[CH2:43][CH2:44][CH2:45][CH2:46][CH:41]4[CH2:40][CH2:39][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)=[O:30])[CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN([C@H]2c3ccc(Cl)cc3CCc3cccnc32)C[C@@H]1C(=O)O
Reactant: c1cn(CCC2CCCCN2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN([C@H]2c3ccc(Cl)cc3CCc3cccnc32)C[C@@H]1C(=O)N1CCCCC1CCn1ccnc1
Temperature: 25 °C
Reaction time: 286 h
Yield: 34 %

Procedure:
Sodium 1,1-dimethylethyl 4-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(S)-yl)-2(R)-carboxy-1-piperazinecarboxylate (prepared as described in Preparative Example 6 (sodium salt)) (0.5239 g, 1.09 mmoles), 2-[2-(1H-imidazol-1-yl)ethyl]piperidine (prepared as described in Preparative Example 57, Step D) (0.2544 g, 1.42 mmoles), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.272 g, 1.42 mmoles), 1-hydroxybenzotriazole (0.1918 g, 1.42 mmoles) and 4-methylmorpholine (0.156mL, 1.42 mmoles) were dissolved in anhydrous DMF (23.5 mL) and the mixture was stirred under argon at 25° C. for 286 h. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with 1N NaOH, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 2.5% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (0.2298 g, 32%): HRFABMS: m/z 619.3169 (MH+) (Calcd. m/z 691.3163).
Reaction SMILES: [CH2:1]([CH:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[C:14]#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:26][CH2:27][CH2:28]Br.C([N-]C(C)C)(C)C.[Li+]>C1(C)C=CC=CC=1>[CH2:1]([C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)([CH2:28][CH2:27][Br:26])[C:14]#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: BrCCBr
Reactant: CCCCCCCCCCCCC(C#N)c1ccc(OC)c(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCC(C#N)(CCBr)c1ccc(OC)c(OC)c1

Procedure:
45.2 g (0.1 mole) of α-(n-dodecyl)-α-(2-bromoethyl)-3,4-dimethoxyphenyl-acetonitrile (obtained by condensation of α-dodecyl-3,4-dimethoxy-phenylacetonitrile with 1,2-dibromoethane in toluene solution in the presence of lithium diisopropylamide) and 41.8 g of β-(N-ethyl)-3,4-dimethoxyphenethylamine were heated at 150° C. in an oilbath for two hours. 250 ml of toluene were added while the mixture was still hot and the precipitate of β-(N-ethyl)-3,4-dimethoxy-phenethylamine hydrobromide which separated out was filtered off with suction.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>>[CH2:2]([C:18]1[O:19][CH:20]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCCCCCCCCCCBr
Reactant: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCc1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
1-Bromotetradecane (3.0 g, 9.01 mmol) in THF (4 mL) was added dropwise and the resulting solution was warmed to room temperature and stirred overnight. The reaction was quenched with a saturated solution of NH4Cl (5 mL). The organic layer was removed and the aqueous layer extracted with ether (3×5 mL). The combined organic layers were washed with a saturated solution of NaHCO3 (1×5 mL), brine (1×5 mL), dried over MgSO4, filtered and concentrated. The crude residue was passed through a small silica gel plug and recrystallized in methanol to afford the 2-(octadecyl)furan compound (22) (2.61 g, 90% yield).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.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>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(Br)c2nsnc12
Reactant: OB(O)c1cccs1
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: CCO
Solvent: O
Solvent: COCCOC
Product: c1csc(-c2ccc(-c3cccs3)c3nsnc23)c1

Procedure:
A solution of 4,7-dibromobenzo[c][1,2,5]thiadiazole (3.0 g, 10.2 mmol) and thiophen-2-ylboronic acid (2.87 g, 22.4 mmol) in 150 mL of 1,2-dimethoxyethane and 50 mL anhydrous ethanol was carefully degassed by bubbling nitrogen through the solution. Next, 7.16 g (67.2 mmol) of sodium carbonate dissolved in 30 mL water was added. The resulting emulsion was degassed, and the catalyst Pd(PPh3)4 (200 mg, 0.17 mmol) was added. Afterwards, the mixture was refluxed under nitrogen overnight. After removal of the organic solvent by reduced pressure, the mixture was poured into water (300 mL) and was extracted with chloroform (3×40 mL). The organic phase was washed with water (30 mL), dried over magnesium sulphate, and the solvent was removed in vacuo. Purification by flash silica gel column chromatography [hexane:chloroform=1:1 (v/v)] followed by recrystallization from hexane/dichloromethane (DCM) yielded orange crystals of TBT (2.6 g, 84.9%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH:34][CH3:35])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:34]([CH3:35])[CH:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: CNC1CCN(C)CC1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN1CCC(N(C)C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.6 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (60 mg, 0.16 mmol) in DMF (1 mL) were added 1-methyl-4-(methylamino)piperidine (23 mg, 0.18 mmol), diisopropylethylamine (DIPEA) (63 μL, 0.36 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (75 mg, 0.20 mmol). The solution obtained was stirred at room temperature for 1 hr then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, gradient 1% Et3N in 10-20% MeOH/ethyl acetate) yielding Compound 51 as a solid (2 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C([Li])(C)(C)C.CCCCC.[C:28]1(=[O:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CCOCC>[OH:34][C:28]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Brc1ccc2[nH]cc(CCN3CCCC3)c2c1
Reactant: O=C1CCCCC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: OC1(c2ccc3[nH]cc(CCN4CCCC4)c3c2)CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
A solution of 5-bromo-3-(2-pyrrolidinylethyl)-1H-indole (Example 3b, 303 mg, 1.03 mmol) in ether (12.5 mL) was added to KH (42.9 mg, 1.07 mmol) at 0° C. After stirring at 0° C. for 20 minutes, the reaction mixture was cooled to -78° C. and a solution of tert-butyllithium in pentane (1.7 M, 0.22 mL, 2.1 mmol) was added dropwise. The reaction mixture was stirred at -78° C. for 30 minutes prior to the addition of cyclohexanone (0.22 mL, 2.1 mmol). The reaction was quenched by the addition of pH 7 buffer and the product was extracted into ethyl acetate, washed with water and brine, and dried over sodium sulfate. After removal of the solvent in vacuo, flash chromatography (silica, 5-10% 2M methanolic ammonia in dichloromethane) yielded 5-(1-hydroxycyclohex-1-yl)-3-(2-pyrrolidinylethyl)-1H-indole (116.4 mg, 36%); HRMS-FAB+ for C20H28N2O: calculated MH+ :313.22800; found MH+ :313.23151.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:10]=2[F:23])[CH:5]=[CH:4][N:3]=1.CC([O-])(C)C.[Na+].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].Cl[Pd]Cl>[C:18]([O:17][C:16](=[O:22])[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:7]=2)=[C:10]([F:23])[CH:11]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(NCc3ccccc3)c2)c(F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 16.6 %

Procedure:
tert-Butyl 4-(2-chloropyridin-4-yloxy)-3-fluorophenylcarbamate (0.100 g, 0.295 mmol, 1.0 eq) was added to a degassed solution of dppf.PdCl2 (Matrix Scientific, 0.011 g, 0.0148 mmol, 0.05 eq), dppf (0.012 g, 0.022 mmol, 0.075 eq), and NaOt-Bu (0.040 g, 0.414 mmol, 1.4 eq) in toluene at room temperature. Benzylamine (0.045 mL, 0.414 mmol, 1.4 eq) was added to the reaction mixture and the resulting solution was stirred at 80° C. for 4 h. The reaction mixture was cooled to room temperature, quenched with 1N HCl and the solution extracted with CHCl3 (3×50 mL). The combined organic extracts were washed with 1 N NaOH (70 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Merck, 40-63 μM, 230-240 mesh, eluting 2:1 hexane/ethyl acetate) to afford the title compound (0.020 g, 17%). 1H NMR (CDCl3) δ 7.80-7.90 (m, 1H), 7.35-7.45 (m, 1H), 7.19-7.24 (m, 3H), 6.91-6.93 (m, 2H), 6.59 (br m, 1H), 6.10-6.20 (m, 1H), 5.75 (br m, 1H), 5.30-5.40 (m, 1H), 4.34 (s, 2H), 1.46 (s, 9H); MS(ESI+) m/z 410 (M+H)+; HRMS (ESI+) calcd.: 410.1880, found: 410.1884.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=[O:30])[CH3:29].[Na+].C(O)C=O.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[OH:30][CH2:28][CH2:29][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([I:1])=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=CCO
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCN(CCO)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 83 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), glycoaldehyde (155 mg, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 43 mg (83%) of the title compound as a yellow solid. MS (ESI) m/z 519.2 (M+H)+1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH3:12].[H][H]>CCO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH3:12]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(N)cc1C
Reaction time: 0.17 h

Procedure:
To the solution of 1-methoxy-2-methyl-4-nitrobenzene (10 g, 60 mmol) in EtOH and EtOAc (250 mL, 3:2) was added 10% Pd/C (2 g). The mixture was stirred for 24 h under one atmosphere of hydrogen. Celite was added and the mixture was stirred for 10 min. The mixture was filtered through a pad of Celite. Concentration under reduced pressure gave 4-methoxy-3-methylaniline. LCMS-ESI+ (m/z): 138.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12]([C:14]2[S:18][CH:17]=[N:16][CH:15]=2)=[O:13])[CH3:10])=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH:26]1([O:30][C:31]2[N:36]=[CH:35][C:34]([C:37]#[CH:38])=[CH:33][N:32]=2)[CH2:29][CH2:28][CH2:27]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH:26]1([O:30][C:31]2[N:32]=[CH:33][C:34]([C:37]#[C:38][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12]([C:14]4[S:18][CH:17]=[N:16][CH:15]=4)=[O:13])[CH3:10])=[CH:4][CH:3]=3)=[CH:35][N:36]=2)[CH2:27][CH2:28][CH2:29]1
Reactant: C#Cc1cnc(OC2CCC2)nc1
Reactant: CC(Cc1ccc(I)cc1)NC(=O)c1cncs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(Cc1ccc(C#Cc2cnc(OC3CCC3)nc2)cc1)NC(=O)c1cncs1
Temperature: 0 °C

Procedure:
100 mg (0.27 mmol) thiazole-5-carboxylic acid (2-(4-iodophenyl)-1-methylethyl)-amide (I76) are added to 2.0 mL THF and cooled down to 0° C. 2.87 mg (4.00 μmol) bis(triphenylphosphine)palladium dichloride, 1.02 mg (5.00 μmol) CuI, 90.6 μL (0.65 mmol) diisopropylamine and finally 51.5 mg 2-cyclobutoxy-5-ethynyl-pyrimidine (I25.7) are added and the reaction mixture is stirred at r.t. over night. The solvent is removed in vacuo and the residue is dissolved in EtOAc and washed with diluted ammonia solution (1×) and water (2×). The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The crude product is purified by HPLC (MeOH/H2O/TFA).