Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:24])[C:9]=2[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:11]=1C(O)=O.CC1NC2CCCC(=O)C=2C(C2C=CC=C([N+]([O-])=O)C=2)C=1C(OCCC#N)=O.[OH-].[Na+]>COCCOC.O>[CH3:1][C:2]1[NH:3][C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:24])[C:9]=2[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[CH:11]=1
Reactant: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1
Agent: CC1=C(C(=O)OCCC#N)C(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CC1=CC(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1
Reaction time: 20 h

Procedure:
2-Methyl-4-(3-nitrophenyl) -5-oxo-1,4,5, 6,7,8-hexa-hydro-3-quinolinecarboxylic acid. To a suspension of 2-cyanoethyl 2-methyl-4-(3-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydro-3-quinolinecarboxylate (0.47 g) in ethylene glycol dimethyl ether (2 mL) was added 1N sodium hydroxide (4 mL). The mixture was stirred for 20 h, during which time all of the solid went into solution. The mixture was diluted with water, washed with ethyl acetate, and acidified by addition of concentrated hydrochloric acid. The resulting precipitate was collected by vacuum filtration and dried to give the acid as a yellow solid (0.31 g); mp 253°-255° C.; MS: 328 (M); NMR: 1.63-2.00 (m,2, CH2), 2.20 (m,2, CH2), 2.31 (s,3, CH3), 2.49 (m,2, CH2), 5.01 (s,1, CH), 7.49-7.61 (m,2, Ar), 7.97 (m,2, Ar), 9.24 (s, 1, NH). Analysis for C17H16N2O5 : Calculated: C, 62.19; H, 4.91; N, 8.53; Found.: C, 62.16; H, 5.02; N, 8.33.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12]/[CH:13]=[C:14](/[C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)\[CH3:15])=[CH:7][CH:6]=1.C(O)C>[OH-].[Na+].Cl.C(OCC)(=O)C>[O:22]([C:19]1[CH:20]=[CH:21][C:16](/[C:14](/[CH3:15])=[CH:13]/[CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:10][CH:9]=2)=[CH:17][CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)Cc1ccc(OC/C=C(\C)c2ccc(Oc3ccccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C/C(=C\COc1ccc(CC(=O)O)cc1)c1ccc(Oc2ccccc2)cc1
Yield: 80 %

Procedure:
(E)-{4-[3-(4-Phenoxy-phenyl)-but-2-enyloxy]-phenyl}-acetic acid methyl ester (example 20 (150 mg, 0.4 mmol) was suspended in 1N NaOH (1 mL) and ethanol (5 ml) and stirred for 24 h at room temperature. The mixture was diluted with 1N HCl (1 mL) and ethyl acetate (10 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL) The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to give 116 mg (80%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:35]=[CH:34][C:26]2[O:27][CH:28]([C:31](O)=[O:32])[CH2:29][O:30][C:25]=2[CH:24]=1>>[OH:22][C:23]1[CH:35]=[CH:34][C:26]2[O:27][CH:28]([C:31]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:32])[CH2:29][O:30][C:25]=2[CH:24]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=C(O)C1COc2cc(O)ccc2O1
Product: O=C(C1COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 80 %

Procedure:
That compound is obtained a yield of 80% starting from 1-[bis(4-fluorophenyl)methyl]piperazine and 6-hydroxy-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>ClCCl>[CH3:22][C:8]1[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]2[C:15]([C:7]=1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([C:33]([F:32])([F:43])[F:44])=[CH:35][CH:36]=3)=[CH:24][CH:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(N)cc2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)c2ccccc21
Yield: 74.8 %

Procedure:
In a dry reaction vessel, ethyl 2-[3-(4-aminobenzyl)-2-methyl-1H-indol-1-yl]acetate (1.0 g, 3.11 mmol) was added, and dissolved in 15 mL dichloromethane. Triethylamine (1.3 mL, 9.34 mmol) was added, and in an ice bath a dichloromethane solution dissolving 4-trifluoromethylbenzoyl chloride (0.649 g, 3.11 mmol) was added slowly. After completion of dropwise addition, it was reacted in an ice bath for 4 h, and filtered. An aqueous solution of sodium bicarbonate was added, extracted with dichloromethane, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 1.15 g, at a yield of 74.9%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:63]1([CH:69]2[CH2:74][CH2:73][S:72](=[O:76])(=[O:75])[NH:71][CH2:70]2)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[O:75]=[S:72]1(=[O:76])[CH2:73][CH2:74][CH:69]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH2:70][N:71]1[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: O=S1(=O)CCC(c2ccccc2)CN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CC(c3ccccc3)CCS2(=O)=O)cc([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 59.9 %

Procedure:
A flask was charged under nitrogen with methyl 3-bromo-5-nitrobenzoate (D11) (136 mg, 0.52 mmol, 1,1 equiv), Cs2CO3 (216 mg, 0.66 mmol, 1.4 equiv), tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.023 mmol, 0.05 equiv), Xantphos (27 mg, 0.047 mmol, 0.1 equiv) and toluene (10 ml). 4-phenyltetrahydro-2H-1,2-thiazine 1,1-dioxide (J. Morris, D. G. Wishka J. Org. Chem. 1991, 56, 3549-3556, 100 mg, 0.47 mmol, 1 equiv) was then added and the resulting mixture was stirred at 120° C. for 5 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between H2O and AcOEt and the aqueous phase was re-extracted with AcOEt. The combined organic solutions were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 7/3) gave methyl 3-(1,1-dioxido-4-phenyltetrahydro-2H-1,2-thiazin-2-yl)-5-nitrobenzoate (B123) (110 mg, 60%) as a yellow oil. [M+H+ NH3]+=408.3, RT=3.24 min
Reaction SMILES: C[O:2][C:3]1[C:4]2[C:5]3[C:6]([C:25](=[O:35])[N:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])[N:27]=3)=[CH:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[CH:23][CH:22]=[N:21]4)=[CH:16][CH:15]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[OH:2][C:3]1[C:4]2[C:5]3[C:6]([C:25](=[O:35])[N:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])[N:27]=3)=[CH:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[CH:23][CH:22]=[N:21]4)=[CH:16][CH:15]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc2c1c1nn(-c3ccccc3C)c(=O)c-1cn2Cc1ccc(-n2cccn2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1-n1nc2c3c(O)cccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
9-(Methyloxy)-2-(2-methylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 723, 37 mg, 0.80 mmol) was dissolved in dichloromethane (5 mL) and cooled to −78° C. Boron tribromide (0.24 mL, 1 M dichloromethane solution, 0.24 mmol, 3 equiv) was added and the mixture was stirred for 3 hours at −78° C. The mixture was then warmed to −40° C. and stirred for an additional 30 minutes. The acetonitrile/dry ice bath was removed, the mixture was warmed to ambient temperature and stirred for 30 minutes. Additional boron tribromide (0.24 mL, 1 M dichloromethane solution, 0.24 mmol, 3 equiv) was added and the mixture was stirred for an additional 45 minutes at ambient temperature. The mixture was treated with sodium bicarbonate (6 mL, aqueous saturated) slowly over 5 minutes, stirred for 30 minutes at ambient temperature and then poured into sodium bicarbonate (50 mL, aqueous saturated). The aqueous layer was extracted with dichloromethane (3×100 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatograph (100:0 to 90:10 dichloromethane:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 9.71 (1H, s), 8.51 (1H, s), 7.91 (1H, d, J=1.9 Hz), 7.74-7.72 (3H, m), 7.47-7.45 (1H, m), 7.39 (1H, t, J=8.5 Hz), 7.36-7.30 (5H, m), 7.01 (1H, d, J=8.3 Hz), 6.94 (1H, d, J=8.6 Hz), 6.48 (1H, m), 5.46 (2H, s), 2.35 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 448.1785 [(M+H)+; calculated for C27H22N5O2: 448.1768].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[CH3:20][C@@:10]([S:16]([CH3:19])(=[O:17])=[O:18])([CH2:9][CH2:8][N:4]1[CH:3]=[C:2]([CH3:1])[CH:6]=[N:5]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cc1cn[nH]c1
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@](C)(CCn1cc(C)cn1)S(C)(=O)=O
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of the 4-methylpyrazole (143 mg, 1.74 mmol, 1 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (500 mg 1.74 mmol, 1 eq) in THF (10 mL) was added cesium carbonate (2.27 g, 6.96 mmol, 4 eq). The resulting suspension was heated to 55° C. and allowed to stir overnight. The reaction was then diluted with EtOAc (10 mL) and the mixture filtered through a pad of celite, which was eluted with ˜10 mL of EtOAc. The crude material was purified by flash chromatography on a 40 g silica gel column eluting with an heptane/ethyl acetate/MeOH gradient) to give ethyl (2R)-2-methyl-4-(4-methyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoate which was used directly in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.27 (s, 1H), 7.13 (s, 1H), 4.30-4.11 (m, 2H), 3.03 (s, 3H), 2.80-2.71 (m, 1H), 2.51-2.41 (m, 1H), 2.04 (s, 3H), 1.66 (s, 3H). LC-MS M+H+289.4.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[Cl:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:15]=1[C:16](Cl)=[O:17].OS([O-])(=O)=O.[K+]>C1COCC1>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:16](=[O:17])[C:15]2[CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[C:21]([F:23])=[CH:22][C:14]=2[Cl:13])=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4-trifluoromethoxy-aniline (0.82 mL, 5.9 mmol), TEA (2.07 mL, 15 mmol) and THF (20 mL) is slowly dropped to the crude 2-chloro-4-fluoro-5-nitro-benzoic acid chloride (1.40 g, 5.9 mmoll) in 30 mL THF. The mixture is stirred for 1 h, poured into ice water and acidified to pH3 with KHSO4. The mixture is concentrated and the resulting precipitate is collected by filtration, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=2[F:43])=[O:34])=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH:19]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:20]([OH:22])=O)=[O:17])[CH:12]=2)[CH:6]=1.CN(C(O[N:52]1N=N[C:54]2C=CC=N[C:53]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>O1CCCC1.O>[CH2:53]([NH:52][C:20](=[O:22])[CH:19]([NH:18][C:16]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:29]=[C:30]([C:33]([NH:35][C:36]4[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=4[F:43])=[O:34])[CH:31]=[CH:32][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)[NH:15][CH:14]=1)=[O:17])[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:54]
Reactant: COC(=O)CCC(NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCNC(=O)C(CCC(=O)OC)NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-methoxy-5-oxopentanoic acid (260 mg, 0.44 mmol) in 20 ml of anhydrous tetrahydrofuran were added HATU (200 mg, 0.53 mmol) and N,N-diisopropylethylamine (170 mg, 1.32 mmol). The mixture was heated at 60° C. for 15 minutes and cooled to room temperature, followed by addition of 2-Methylamine solution in THF (0.44 ml, 0.88 mmol). The mixture was stirred for another 5 minutes, and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 2˜5% methanol in chloroform to give methyl 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-oxopentanoate as white solid. Yield: 127 mg, 47%.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[N-:15]=[N+:16]=[N-:17].[Na+]>CCO.O>[N:15]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[N+:16]=[N-:17]
Reactant: CCOP(=O)(CCOCCBr)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CCOCCN=[N+]=[N-])OCC

Procedure:
To a solution of diethyl 2-(2-bromoethoxy)ethylphosphonate (1 eq) in EtOH (0.3 M) was added sodium azide (5 eq) in water (2 M). The reaction mixture was heated at reflux overnight. The mixture was then diluted with water, extracted with ethyl acetate. The organic layer was washed with 5% citric acid, saturated NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 80-100% EtOAc/Hex to give the product as colorless oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:58]=[CH:57][C:13]([CH2:14][N:15]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[C:24]([NH:40][C:41]4[CH:42]=[CH:43][C:44]([NH2:47])=[N:45][CH:46]=4)=[N:25][CH:26]=[C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:32][CH2:31]4)[CH:28]=3)[N:17]=2)=[CH:12][CH:11]=1.N1C=CC=CC=1.O>CN(C=O)C>[CH3:56][O:55][C:52]1[CH:51]=[CH:50][C:49]([CH2:48][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:58][CH:57]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[C:24]([NH:40][C:41]4[CH:42]=[CH:43][C:44]([NH:47][C:1](=[O:3])[CH3:2])=[N:45][CH:46]=4)=[N:25][CH:26]=[C:27]([CH2:29][N:30]4[CH2:31][CH2:32][N:33]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:34][CH2:35]4)[CH:28]=3)[N:17]=2)=[CH:54][CH:53]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(N)nc3)n2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(C)=O)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.3 %

Procedure:
Acetic anhydride (Aldrich) (0.13 mL, 1.4 mmol) was added slowly at 0° C. to a stirred solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)pyridine-2,5-diamine (0.0864 g, 0.122 mmol) and pyridine (0.60 mL, 7.4 mmol) in DMF (2mL). The mixture was stirred at rt for 1.5 h. Water was added and the resulting solid was collected by filtration and washed with water and air-dried to give N-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)pyridin-2-yl)acetamide (0.0857 g, 94% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.86 (s, 1H); 8.72 (d, J=2.15 Hz, 1H); 8.51 (d, J=2.54 Hz, 1H); 8.24 (d, J=2.35 Hz, 1H); 8.09 (s, 1H); 7.96 (d, J=2.15 Hz, 1H); 7.91 (s, 1H); 7.20 (dd, J=8.22, 6.26 Hz, 4H); 6.86 (t, J=8.61 Hz, 4H); 4.84 (d, J=8.80 Hz, 4H); 3.80 (d, J=7.43 Hz, 6H); 3.51 (s, 2H); 3.18 (br. s., 4H); 2.71 (s, 3H); 2.60 (s, 3H); 2.55 (t, J=4.21 Hz, 4H); 2.20 (s, 3H). m/z (ESI, +ve ion) 753.0 (M+H)−.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)CCC.[F:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[N:49]=[C:48]([C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[C:52](Br)[CH:51]=3)[O:47][N:46]=2)=[N:43][CH:44]=1>O1CCCC1>[F:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[N:49]=[C:48]([C:50]3[CH:51]=[C:52]([C:6]4[N:7]=[CH:8][N:9]([C:11]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:10]=4)[CH:53]=[C:54]([F:56])[CH:55]=3)[O:47][N:46]=2)=[N:43][CH:44]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Fc1ccc(-c2noc(-c3cc(F)cc(Br)c3)n2)nc1
Solvent: C1CCOC1
Product: Fc1ccc(-c2noc(-c3cc(F)cc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)c3)n2)nc1
Temperature: 100 °C
Yield: 23.5 %

Procedure:
To the solution of 4-Tributylstannyl-1-trityl-1H-imidazole (106 mg, 0.18 mmol) in tetrahydrofuran (5 ml) added 3-(5-Fluoro-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (50.0 mg, 0.15 mmol) and tetrakis(triphenylphoshine)palladium (O) (17.1 mg, 0.01 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 100° C. under argon overnight. The reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was purified on silica gel using 30% ethyl acetate in hexanes to isolate 3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(1-trityl-1H-imidazol-4-yl)phenyl)-1,2,4-oxadiazole (20.0 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].C[N:11]1[CH2:20][CH2:19][C@H:18]2[C@H:13]([C:14]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:15]=3[C:16](=[O:21])[CH2:17]2)[CH2:12]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH3:27][C:22]1[C:15]2[C:16](=[O:21])[CH2:17][CH:18]3[CH:13]([C:14]=2[CH:25]=[C:24]([CH3:26])[CH:23]=1)[CH2:12][N:11]([C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[CH2:20][CH2:19]3
Reactant: Cc1cc(C)c2c(c1)[C@@H]1CN(C)CC[C@@H]1CC2=O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1)C1CN(C(=O)OCC(Cl)(Cl)Cl)CCC1CC2=O
Temperature: 25 °C
Yield: 97.3 %

Procedure:
a 2.1) 0.76 ml (5.65 mmol) of 2,2,2-trichloroethyl chloroformate was added at 1000 to a suspension of 500 mg (2.26 mmol) of (+)-cis-2,7,9-trimethyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one and 120 mg of K2CO3 in 20 ml of toluene and the mixture was heated at reflux for 16 hours. Subsequently, the solution was cooled to room temperature and poured on to 40 ml of ice-water. The aqueous phase was extracted twice with 50 ml of ethyl acetate, dried (MgSO4), filtered and evaporated. Chromatography of the residue (silica gel, hexane/ethyl acetate 4:1) yielded 890 mg (97%) of 2,2,2-trichloroethyl 7,9-dimethyl-6-oxo-3,4,4a,5,6,10b-hexahydro-1H-benzo[h]isoquinoline-2-carboxylate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[C@@H:9]([CH3:15])[NH:8][C@H:7]([CH3:16])[CH2:6]2.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>C(C(C)=O)C.CCOCC>[CH2:17]([N:8]1[C@H:7]([CH3:16])[CH2:6][C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:9]1[CH3:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc2c(c(OC)c1)[C@@H](C)N[C@H](C)C2
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Solvent: CCOCC
Product: COc1cc2c(c(OC)c1)[C@@H](C)N(Cc1ccccc1)[C@H](C)C2
Yield: 95 %

Procedure:
Into a stirred solution of (1R, 3R)-1,2,3,4-tetrahydro-6,8-dimethoxy-1,3-dimethyl-isoquinoline (114 mg, 0.5 mmol) and benzyl chloride (137 mg, 1.1 mmol) in methyl ethyl ketone was added K2CO3 (320 mg, 2.3 mmol). The resulting mixture was heated to reflux for 24 h, after which time it was cooled down and poured into H2O. Et2O was added and the organic layer was washed with H2O, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by MPLC (hexanes/EtOAc/Et3N; 9:1:0.3) to yield N-benzyl-(1R, 3R)-1,2,3,4-tetrahydro-6,8-dimethoxy-1,3-dimethyl-isoquinoline (148 mg, 93%) as a colorless oil; 1H NMR (500 MHz, CDCl3): δ7.40-7.20 [m, benzyl ArH], 6.28 [d, J=2.0 Hz, ArH(7)], 6.23 [d, J=2.0 Hz, ArH(5)], 3.66 [q, J=6.5 Hz, ArCHCH3 ], 3.82 [d, J=14.0 Hz, NCHaHbPh], 3.78 [s, O(6)CH3 ], 3.70 [s, O(8)CH3, 3.50 [ddq, J=10.5, 5.0 and 6.5 Hz, CHaHbCHCH3 ], 3.29 [d, J=14.0 Hz, NCHaHbPh], 2.63 [dd, J=17.0 and 10.5 Hz, CHaHbCH], 2.58 [dd, J=17.0 and 5.0 Hz, CHaHbCH], 1.30 [d, J=6.5 Hz, CH3 (1)], and 1.25 [d, J=6.5 Hz, CH3 (3)]; 13C NMR (75 MHz, CDCl3): δ158.5, 158.4, 141.7, 136.8, 128.4 [2C], 128.1 [3C], 126.4, 104.1, 96.4, 55.2, 55.1, 51.4, 49.8, 45.8, 32.6, 20.0, and 19.5; LRMS (EI): m/z 296 (M+ --CH3, 100), and 91 (44); IR (neat NaCl plates): 2965, 1605, and 1148 cm-1 ; Anal. calcd for C20H25NO2 : C, 77.14; H, 8.09. Found: C, 77.30; H, 8.06.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].N1C=C[C:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30](=[O:36])[NH:31]3)=CC=1>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:29]3[C:28]4[C:32](=[CH:33][CH:34]=[CH:35][C:27]=4[CH3:24])[NH:31][C:30]3=[O:36])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(C)c43)c(C)c2C1=O
Yield: 64.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-pyridin-4-yl-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 5-(2-diethylamino-ethyl)-3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (48 mg, 64.9%) as an orange solid.