Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[OH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[OH:33])=[N:3][CH:4]=[C:5]2[F:32])(=[O:13])=[O:14]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Reactant: OB(O)c1ccccc1O
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: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4O)ncc(F)c3c2)c(OC)c1

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate PPP; 0.075 g, 0.152 mmol), (2-hydroxyphenyl)boronic acid (0.031 g, 0.228 mmol), tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.015 mmol), and potassium carbonate (0.105 g, 0.759 mmol). Dioxane (0.759 mL) and Water (0.253 mL) were added; the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-100% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-4-fluoro-1-(2-hydroxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide. (ESI) 522.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:13]([OH:15])=O.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:13]([C:5]3[O:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:4]=3[CH2:3][O:2][CH3:1])=[O:15])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: COCc1c(C(=O)O)oc2ccccc12
Product: COCc1c(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)oc2ccccc12

Procedure:
With a procedure similar to the example above, 4-{4-[(3-methoxymethyl-benzofuran-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 3-methoxymethyl-benzofuran-2-carboxylic acid and 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. LCMS calcd for C26H31N3O5 (m/e) 465, obsd 466 (M+H).
Reaction SMILES: BrC1C(=O)[NH:4][C:5](=[O:8])[NH:6]C=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25]Br>ClC(Cl)C>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][NH:4][C:5]([NH2:6])=[O:8]
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Reactant: Fc1cccc(F)c1CBr
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CC(Cl)Cl
Product: NC(=O)NCc1c(F)cccc1F
Temperature: 80 °C
Yield: 84.5 %

Procedure:
A suspension of 5-bromouracil (18.45 g, 96.6 mmol) in 300 mL of dichloroethane was treated with N,O-bis(trimethylsilyl)acetamide (48 mL, 39.5 g, 194 mmol). The reaction mixture was heated at 80° C. for 3 hr under the nitrogen. The solution was cooled down to ambient temperature, 2,6-difluorobenzyl bromide (25 g, 120 mmol) was added and the reaction mixture was heated at 80° C. overnight under the protection of nitrogen. The reaction was cooled down, quenched with MeOH (15 mL), and partitioned between dichloromethane (500 mL) and water (250 mL). The organic layer was washed with brine, dried (sodium sulfate), and evaporated to give a solid. The crude product was triturated with ether, filtered, and washed with ether three times to give compound 1 (15.2 g, 50%) as a white solid; MS (CI) m/z 316.90, 318.90 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]1[CH:11]=[CH:12][C:13](B2OC(C)(C)C(C)(C)O2)=[C:14]([CH:17]=1)[C:15]#[N:16]>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].O>[Br:8][C:6]1[CH:7]=[C:2]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:17][C:14]=2[C:15]#[N:16])[CH:3]=[N:4][CH:5]=1
Reactant: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Reactant: Brc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(F)ccc1-c1cncc(Br)c1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A solution of 3,5-dibromopyridine (1.0 g, 4.2 mmol) and 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.95 g, 3.8 mmol) in 1,2-dimethoxyethane (20 ml) and 2N sodium carbonate solution (10 ml) was degassed with nitrogen for 30 min. Tetrakis-(triphenylphosphine)palladium(0) (89 mg, 0.08 mmol) was added and the mixture heated under reflux for 18 h. The mixture was allowed to cool to ambient temperature, diluted with water (10 ml) then extracted with ethyl acetate (2×100 ml). The organics were combined, dissolved in phophorus oxychloride (50 ml) and heated at 100° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature and concentrated. The residue was treated with ice, and the resulting solution was layered with ethyl acetate (30 ml) and made basic by the addition of solid sodium hydrogencarbonate. The layers were separated, and the aqueous extracted further with ethyl acetate (75 ml). The organics were combined, washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give a colourless oil. The oil was purified by flash column chromatography on silica, eluting with isohexane on a gradient of ethyl acetate (20-50%), to give 2-(5-bromopyridin-3-yl)-5-fluorobenzonitrile (0.95 g, 81%) as a white solid: δH (360 MHz, CDCl3) 7.44-7.46 (1H, m), 7.49-7.54 (2H, m), 8.02 (1H, s), 8.67 (1H, d, J 1.8), 8.78 (1H, d, J 1.8).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][NH:22][CH2:23]4)[N:14]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].BrN1C(=O)CCC1=O.[OH-].[Na+]>C(Cl)Cl>[CH:23]1[C:24]2[C:19](=[C:18]([C:15]3[N:14]=[C:13]([C:10]4[CH:11]=[CH:12][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[C:6]([CH:9]=4)[C:7]#[N:8])[O:17][N:16]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:21][N:22]=1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNC4)no2)cc1C#N
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN=C4)no2)cc1C#N
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 2-[(1-methylethyl)oxy]-5-[3-(1,2,3,4-tetrahydro-5-isoquinolinyl)-1,2,4-oxadiazol-5-yl]benzonitrile (Preparation 7, 50 mg, 0.139 mmol) and N-bromosuccinimide (29.6 mg, 0.166 mmol) in DCM (5 mL) was heated at reflux for 3 h, then cooled to room temperature. 2M aqueous NaOH (5 mL) was added, and the layers separated. The aqueous was extracted with DCM (5 mL) and the organic layers combined. Concentration in vacuo gave the title compound as a yellow solid (47.8 mg). 1H NMR (400 MHz, CDCl3) δ 8.52 (1H, t), 8.43 (1H, d), 8.34 (1H, dd), 8.23 (1H, dd), 7.55-7.51 (2H, m), 7.14 (1H, d), 4.81 (1H, sept), 3.86 (2H, td), 3.31 (2H, t), 1.48 (6H, d); m/z (ES) 359 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])([O-:3])=[O:2].OS(O)(=O)=O.[CH2:19](O)[CH3:20]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12])([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 82 %

Procedure:
In ethanol (250 ml) was dissolved (2-nitrophenyl)acetic acid (18.5 g, 0.102 mmol), and to the resulting solution was added concentrated H2SO4 (0.1 ml). The mixture was heated under reflux for 24 hours. The reaction mixture was cooled to room temperature and then, diluted with ethyl acetate. The diluted solution was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, whereby ethyl (2-nitrophenyl)acetate (17.4 g, 82%) was obtained as a colorless solid.
Reaction SMILES: C(C1C=C(C=CC=1OC(C)C)C(O)=O)#N.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Si](OCC1C=C(C=CN=1)C(=N)NO)(C(C)(C)C)(C)C.[Si]([O:56][CH2:57][C:58]1[CH:59]=[C:60]([CH:79]=[CH:80][N:81]=1)[C:61](=[NH:78])[NH:62][O:63][C:64](=O)[C:65]1[CH:70]=[CH:69][C:68]([O:71][CH:72]([CH3:74])[CH3:73])=[C:67]([C:75]#[N:76])[CH:66]=1)(C(C)(C)C)(C)C>CN(C=O)C.CO>[OH:56][CH2:57][C:58]1[CH:59]=[C:60]([C:61]2[N:78]=[C:64]([C:65]3[CH:70]=[CH:69][C:68]([O:71][CH:72]([CH3:74])[CH3:73])=[C:67]([CH:66]=3)[C:75]#[N:76])[O:63][N:62]=2)[CH:79]=[CH:80][N:81]=1
Reactant: CC(C)Oc1ccc(C(=O)ONC(=N)c2ccnc(CO[Si](C)(C)C(C)(C)C)c2)cc1C#N
Agent: CC(C)(C)[Si](C)(C)OCc1cc(C(=N)NO)ccn1
Agent: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccnc(CO)c3)no2)cc1C#N
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 8 %

Procedure:
Prepared using General Procedure 2. To a solution of 3-cyano-4-isopropoxybenzoic acid (0.033 g, 0.16 mmol) in DMF (1.0 mL) was added HOBt (0.036 g, 0.23 mmol) and EDC (0.045 g, 0.23 mmol) at room temperature. The reaction was stirred for 0.5 h until the complete formation of the HOBt-acid complex. 2-((Tert-butyldimethylsilyloxy)methyl)-N-hydroxyisonicotinimidamide INT-72 (0.050 g, 0.18 mmol) was added and the mixture was stirred at room temperature for 0.5 h until the formation of the intermediate 2-((tert-butyldimethylsilyloxy)methyl)-N-(3-cyano-4-isopropoxy benzoyloxy)isonicotinimidamide was observed. The reaction mixture was then heated at 85° C. for 4 h. To the cooled reaction mixture MeOH (1.0 mL) was added, and the solution was filtered. The resulting filtrate was purified by preparative HPLC to produce 5.6 mg (8%) of 5-(3-(2-(hydroxymethyl)pyridin-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 71 as the TFA salt. LCMS-ESI (m/z) calculated for C18H16N4O3: 336.3; found 337.1 [M+H]+, tR=7.45 min (Method 2). NMR (400 CD3OD) δ 8.78 (d, J=5.5, 1H), 8.48 (dd, J=10.6, 8.3, 1.4, 3H), 8.23 (dd, J=5.5, 1.6, 1H), 7.48 (d, J=9.0, 1H), 4.93 (s, 2H), 4.89 (m, 1H), 1.48 (d, J=6.1, 6H).
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=[O:11].[Ce].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>CO.[N+]([O-])(O)=O.[Pt]>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[O:11])=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc(C)cc1
Agent: [Pt]
Agent: [Ce+3]
Agent: [Ce]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: COc1ccc(C=O)cc1
Yield: 96 %

Procedure:
A 18.2 g quantity of cerium(III) nitrate is dissolved in 100 ml of methanol containing 10 ml of 65% by weight of nitric acid, and the solution is placed into an anode chamber. A methanol solution containing 10 ml of 65% by weight of nitric acid is placed into a cathode chamber. The cerium salt is electrolyzed with a constant current of 60 mA using platinum electrodes to pass electricity across the electrodes in a quantity of 1.2 F/mole. A 1.22 g of quantity of p-methyl anisole is oxidized with the solution withdrawn from the anode chamber after the electrolysis. The same procedure as in Example 1 is thereafter repeated to obtain 1.306 g of anisaldehyde. Yield: 96.0%.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CS(=O)(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (31.8 mg) obtained in Example 25 and methylsulfonyl chloride (9.3 μl) were reacted and treated in the same manner as in the method described in Example 30 to obtain the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O>[OH-].[K+].CCO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1cccs1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2cccs2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 67.5 %

Procedure:
According to the method of Example 8, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.400 g, 1.56 mmol) was reacted with 2-thiophene carboxaldehyde (0.264 g, 2.35 mmol) in 5.0 mL of 4% KOH in EtOH for 4.5 hours at room temperature to afford 0.369 g (67%) of the title compound as dark yellow crystals, mp 137-138° C.: CI-MS m/e 350 (M+), 351 (M++1);
Reaction SMILES: N#N.[CH2:3]([O:10][C@@H:11]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][OH:18])[O:13][C@H:12]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([OH:24])[C:22]=2[N:21]=[CH:20]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:29][O:30][C:31]1[CH:52]=[CH:51][C:34]([C:35](Cl)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[CH:33][CH:32]=1>N1C=CC=CC=1.ClCCl.CCOC(C)=O.CCCCCC.C(N(CC)CC)C>[CH2:3]([O:10][C@@H:11]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][O:18][C:35]([C:34]2[CH:51]=[CH:52][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[O:13][C@H:12]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([OH:24])[C:22]=2[N:21]=[CH:20]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](OCc2ccccc2)[C@@H]1O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(O)ncnc43)[C@H](OCc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
Under the protection of N2, to a solution of 2′-O-benzylinosine (1.0 g, 2.79 mmol) in 10 mL pyridine was added 4,4′-dimethoxytrityl chloride (2.36 g, 6.98 mmol). The mixture was stirred at room temperature for 2 h. The reaction was diluted with 100 mL dichloromethane and quenched with 100 mL saturated NaHCO3 solution. After the aqueous layer was extracted with dichloromethane (100 mL) three times, the organic layers were combined and evaporated. The residue was purified by flash chromatography (gradient: hexane with EtOAc 0-45%, with 1% triethylamine in both hexane and EtOAc) to produce 1.80 g (2.72 mmol, 98%) product. LCMS: for C38H36N4O7 calculated 660.3. found 661.2 [M+H]+. 1H NMR (600 MHz, CD3CN) δ: 7.83 (s, 1H), 7.80 (s, 1H), 7.39 (m, 2H), 7.23 (m, 12H), 6.82 (m, 4H), 6.02 (d, J=5.0 Hz, 1H), 4.71 (d, J=12.2 Hz, 1H), 4.59 (d, J=12.2 Hz, 1H), 4.54 (dd, J=5.1, 5.1 Hz, 1H), 4.42 (dd, J=9.6, 4.8 Hz, 1H), 4.14 (dd, J=8.4, 4.2 Hz, 1H), 3.64 (m, 1H), 3.57 (m, 1H). 13C NMR (600 MHz, CD3CN) δ: 158.88, 156.87, 145.48, 145.18, 138.51, 136.09, 135.98, 130.23, 128.50, 128.24, 128.16, 128.08, 128.07, 128.04, 128.00, 127.08, 117.58, 117.08, 117.04, 113.264, 86.91, 84.49, 80.70, 7229, 69.84, 63.55, 62.88, 55.15, 52.76.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:27][CH2:26][CH2:25][C:9]32[N:13]([CH3:14])[C:12](=[O:15])[N:11]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:10]3=[O:24])=[CH:4][CH:3]=1.[C:28]([Cu])#[N:29].C(N)CN>CN1C(=O)CCC1>[Cl:23][C:18]1[CH:17]=[C:16]([N:11]2[C:10](=[O:24])[C@:9]3([CH2:25][CH2:26][CH2:27][C@H:8]3[C:5]3[CH:6]=[CH:7][C:2]([C:28]#[N:29])=[CH:3][CH:4]=3)[N:13]([CH3:14])[C:12]2=[O:15])[CH:21]=[C:20]([Cl:22])[CH:19]=1
Reactant: N#C[Cu]
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)C12CCCC2c1ccc(Br)cc1
Solvent: CN1CCCC1=O
Solvent: NCCN
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(C#N)cc1
Temperature: 180 °C

Procedure:
A mixture of 6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (1 g, 2.1 mmol) (Example 1) and CuCN (0.45 g, 5 mmol) in NMP was heated to 180° C. for 6 h. After cooling, the reaction mixture was poured on a mixture of ice and ethylene diamine and extracted twice with DCM. The brown residue was chromatographed over silica gel to yield 4-[(5R*,6S*)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3-diazaspiro[4.4]non-6-yl]benzonitrile as a beige solid. 1H NMR (CDCl3): 7.62 (2H, d, J=8.1 Hz), 7.25-7.3 (3H, m), 6.67 (2H, br s), 3.45 (1H, dd, J1=12.8 Hz, J2=6.4 Hz), 3.16 (3H, s), 2.4-2.7 (1H, m), 1.8-2.4 (5H, m).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17](=[O:24])(=[O:23])[NH:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>>[OH:22][CH2:21][CH2:20][CH2:19][NH:18][S:17]([C:4]1[S:3][CH:2]=[C:6]([C:7]2[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=2[CH3:16])[CH:5]=1)(=[O:23])=[O:24]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCCO)sc2Br)s1
Agent: [Li]CCCC
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)NCCCO)c2)s1
Temperature: -70 °C

Procedure:
N-{5-[2-Bromo-5-(3-hydroxy-propylsulfamoyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (230 mg; 0.51 mmol; 1 eq), is dissolved in anhydrous TBF (20 ml). The reaction mixture is cooled down to −70° C. and put under nitrogen. n-Butyllithium (1.9 ml; 1.6 M; 3.04 mmol; 8 eq) is added dropwise. After 4 hours the reaction is quenched with water. Solvents are evaporated and the resulting crude product is purified by preparative HPLC, affording Compound (32) as a white-off powder (80.2 mg; 32%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:15]2[CH2:20][CH2:19][C:18]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)([CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[CH2:17][CH2:16]2)=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])C.Cl>[OH-].[Na+].O1CCOCC1>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([C:18]2([CH2:21][N:22]3[C:23](=[O:32])[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]3=[O:31])[CH2:17][CH2:16][N:15]([C:7]3[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]4[NH:12][CH:13]=[CH:14][C:8]=34)[CH2:20][CH2:19]2)=[CH:38][CH:37]=1
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1N1CCC(CN2C(=O)c3ccccc3C2=O)(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cnc2[nH]ccc2c1N1CCC(CN2C(=O)c3ccccc3C2=O)(c2ccc(Cl)cc2)CC1
Yield: 97.1 %

Procedure:
4-[4-(4-Chlorophenyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (49 mg, 0.09 mmol) was hydrolysed in a mixture of 2M NaOH (1 mL) and 1,4-dioxane (1 mL) at 80° C. overnight. The solution was acidified by dropwise addition of conc. HCl. Solvents were evaporated and the resulting solid was filtered and washed with water, then dried. A white solid (45 mg) was obtained which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH:16]=[C:17](Br)[C:11]=2[N:10]([CH3:27])[C:9]1=[O:28])(=[O:3])[CH3:2].[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH:16]=[C:17]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:29])[CH:35]=3)[C:11]=2[N:10]([CH3:27])[C:9]1=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=O)c2c(c(Br)cn2Cc2ccc(Cl)cc2)n(C)c1=O
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)OCCCn1c(=O)c2c(c(-c3cccc(Cl)c3)cn2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 3-(7-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (See Compound 34, Step 4, 93 mg, 0.2 mmol), 3-chlorophenylboronic acid (62.4 mg, 0.4 mmol), aq. 2M K3PO4 (0.4 ml, 0.8 mmol) in dioxane (2 mL) was added Pd(dppf)Cl2 (10 mg, 0.013 mmol). The reaction was degassed with nitrogen (3×), heated at 85° C. (MW) for 20 min, cooled to RT, diluted with EA (10 mL) and water (3 mL) then filtered. The filtrate was concentrated to a residue which was purified by chromatography eluted with PE/EA (2:1) to give 3-(5-(4-chlorobenzyl)-7-(3-chlorophenyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (60 mg, 60% yield) as a brown solid. LCMS: MH+ 500 and TR=1.905 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[Si:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([N:35]2[C:39](=[O:40])[C:38]3=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]3[C:36]2=[O:45])=[C:32]([CH:34]=1)[NH2:33])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C(Cl)Cl.CO.[OH-].[NH4+]>C(Cl)Cl.N1C=CC=CC=1>[Si:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([N:35]2[C:36](=[O:45])[C:37]3=[CH:44][CH:43]=[CH:42][CH:41]=[C:38]3[C:39]2=[O:40])=[C:32]([CH:34]=1)[NH:33][C:13]([CH:10]1[CH2:9][CH2:8][N:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH2:12][CH2:11]1)=[O:15])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c(N)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c(NC(=O)C2CCN(c3ccncc3)CC2)c1
Reaction time: 0.75 h
Yield: 76.1 %

Procedure:
1-(4-Pyridyl)piperidine-4-carboxylic acid (176 mg, 0.85 mmol) and thionyl chloride (93 mL, 1.28 mmol) in 5 mL methylene chloride were heated under reflux for 2 h. The mixture was allowed to cool, concentrated in vacuo to a white foam and dried under vacuum. The foam was suspended in dry methylene chloride (5 mL) then added were 5-tert-butyldimethylsilyloxy-2-(phthalimido)aniline (314 mg; 0.85 mmol)(see Example 167, step C, above) as a solution in 5 mL methylene chloride and 1 mL pyridine in several portions. The cloudy mixture was stirred 45 min then passed through a 35×80 mm plug of silica gel eluting first with methylene chloride then with 9:1:0.1 methylene chloride/methanol/ammonium hydroxide. Appropriate fractions were combined, concentrated in vacuo and dried under vacuum to yield 360 mg (76%) of the desired intermediate phthalimide.