Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:8]([NH:22][C:23]2[CH:27]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[NH:25][N:24]=2)=[N:9][C:10]([C:13]2[S:14][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][CH:17]=2)=[N:11][CH:12]=1)(=O)C.[OH-].[Na+].O>CO>[CH:28]1([C:26]2[NH:25][N:24]=[C:23]([NH:22][C:8]3[C:7]([CH2:6][CH2:5][OH:4])=[CH:12][N:11]=[C:10]([C:13]4[S:14][C:15]([S:18]([NH2:19])(=[O:21])=[O:20])=[CH:16][CH:17]=4)[N:9]=3)[CH:27]=2)[CH2:30][CH2:29]1
Reactant: CC(=O)OCCc1cnc(-c2ccc(S(N)(=O)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NS(=O)(=O)c1ccc(-c2ncc(CCO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Yield: 65.6 %

Procedure:
A solution of 2-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-(5-sulfamoylthiophen-2-yl)pyrimidin-5-yl)ethyl acetate (Compound 313) (200 mg, 0.45 mmol, 1.0 equiv.) and NaOH.aq (2 mL) in MeOH (5 mL) was stirred for 1 h at rt. Water was added and the mixture was extracted with EtOAc. The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to yield 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(2-hydroxyethyl)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 239) (120 mg, 66%). LC-MS (m/z)=407.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.77-0.81 (m, 2H), 1.01-1.06 (m, 2H), 1.97-2.01 (m, 1H), 2.89 (t, J=5.6 Hz, 2H), 3.69 (d, J=5.6 Hz, 2H), 6.47 (s, 1H), 7.69 (d, J=4.0 Hz, 1H), 7.98 (s, 2H), 8.23 (s, 1H), 8.34 (d, J=3.2 Hz, 1H), 10.67 (s, 1H)
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)N>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Product: OCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (1.50 g, 6.72 mmol) and 3-chloro-4-(pyridin-2-ylmethoxy)aniline (1.58 g, 6.72 mmol) to give the title compound as a while solid (2.40 g, 87%); NMR Spectrum: 3.80 (t, 2H), 4.32 (t, 2H), 5.30 (s, 2H), 7.26 (d, 1H), 7.36-7.38 (m, 1H), 7.55-7.59 (m, 2H), 7.86-7.90 (m, 2H), 8.28 (s, 1H), 8.48 (br s, 1H), 8.59 (d, 1H); Mass Spectrum: 413 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[C:30](=[O:31])[C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=[CH:22]5)[C:16]=4[CH3:32])=[C:13]([CH3:33])[N:12]=[C:11]([C:34]([NH2:36])=[O:35])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:42]([O:44]CC)=[CH2:43])CCC.C(N(CC)CC)C>O1CCOCC1.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>[C:42]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[C:30](=[O:31])[C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=[CH:22]5)[C:16]=4[CH3:32])=[C:13]([CH3:33])[N:12]=[C:11]([C:34]([NH2:36])=[O:35])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1)(=[O:44])[CH3:43]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(C(N)=O)c2[nH]c3cc(Br)ccc3c2c1-c1cccc(-n2cnc3ccccc3c2=O)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)nc(C)c(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a well degassed mixture of 7-bromo-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.101 g, 0.188 mmol) and Bis(triphenylphosphine)palladium(II) chloride (0.018 g, 0.026 mmol) in 1,4-dioxane (2.0 mL) in a sealed tube was added tributyl(1-ethoxyvinyl)stannane (0.148 mL, 0.450 mmol) followed by triethylamine (0.052 mL, 0.375 mmol). The resulting mixture was evacuated and charged with nitrogen (2×), immersed in an oil bath at 100° C., and stirred overnight. The mixture was diluted with ethyl acetate, filtered through a pad of CELITE®, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL) and stirred with 1 N aqueous hydrochloric acid (2 mL) for 2 h. The solution was concentrated under reduced pressure, and the residue was suspended in water. The pH was adjusted to ˜6 with 1 N sodium bicarbonate, and the suspension was extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture of ethyl acetate and hexane (50%-62%-75%-88%) afforded 7-acetyl-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.051 g, 0.102 mmol, 54% yield) as a pale yellow solid. LC/MS M+1=502.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH:21]([NH:25][C:26](=[O:34])[C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]3)OCC[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[C:9]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH:21]([NH:25][C:26](=[O:34])[C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[CH:22]([CH3:23])[CH3:24])[CH2:16][CH2:15]1)=[O:10]
Reactant: Cc1ccc(C(=O)NC(CN2CCC(C3(c4ccc(Cl)c(Cl)c4)OCCO3)CC2)C(C)C)cc1
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(C(=O)NC(CN2CCC(C(=O)c3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1

Procedure:
A mixture of N-(1-{4-[2-(3,4-dichlorophenyl)-[1,3]dioxolan-2-yl]piperidin-1-yl-methyl}-2-methylpropyl)-4-methylbenzamide (0.4 g, 0.791 mmol), aqueous HCl (10 mL, 6 N), and acetonitrile (10 mL) was refluxed for 2 h. After concentrating the reaction mixture, the residue was stirred with ethyl acetate and water. Sodium hydroxide solution (6 N) was added until the aqueous layer was pH 8. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over magnesium sulfate and concentrated to give N-{1-[4-(3,4-dichlorobenzoyl)-piperidin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide which was converted to the hydrochloride salt by adding 2 molar excess ethereal HCl (1 M) to an ether solution of the free base.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[CH2:8][CH2:7]1)[CH2:2][CH3:3].C[Al](C)C.CCCCCCC.CO[C:22]([C:24]1[N:25]([CH3:41])[N:26]=[C:27]2[C:32]=1[CH:31]=[CH:30][CH:29]=[C:28]2[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])=[O:23].[OH-].[Na+]>C1C=CC=CC=1>[CH:6]1([CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[C:22]([C:24]2[N:25]([CH3:41])[N:26]=[C:27]3[C:32]=2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])=[O:23])[CH2:8][CH2:7]1
Reactant: CCCNCC1CC1
Reactant: COC(=O)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: CCCN(CC1CC1)C(=O)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Temperature: 79 °C
Yield: 47.1 %

Procedure:
To a solution of N-propylcyclopropanemethyl amine (0.69 mL, 4.8 mmol) in 12 mL of benzene was slowly added a 2M solution of trimethylaluminum in heptane (2.4 mL, 4.8 mmol), and the solution was stirred for 75 m. The solution was transferred with a pipette to a solution of 35b (0.200 g, 0.597 mmol) in 10 mL of benzene. The solution was heated to 79° C., stirred for 2 d, then cooled to 0-5° C. A 2 M aqueous NaOH solution (20 mL) was slowly added, and the mixture was extracted with three 20 mL portions of dichloromethane. The combined organic layers were washed with 40 mL of a saturated NaCl solution, dried over MgSO4, filtered, and concentrated to a brown oil. Column chromatography (0→20% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carboxylic acid cyclopropylmethyl-propyl-amide (35c: 0.117 g; 47%) as an oil.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][NH:14][C:13]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1.CN1CCCC1=O.[H-].[Na+].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C@@:35]1([CH2:39][N:40]2[CH:44]=[N:43][CH:42]=[N:41]2)[C@H:37]([CH3:38])[O:36]1>C(OCC)(=O)C>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C@@:35]([OH:36])([CH2:39][N:40]1[CH:44]=[N:43][CH:42]=[N:41]1)[C@H:37]([N:14]1[CH:15]=[CH:16][N:12]([C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)=[CH:7][CH:8]=2)[C:13]1=[O:17])[CH3:38]
Reactant: O=c1[nH]ccn1-c1ccc(-n2ccnn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@@H](n1ccn(-c2ccc(-n3ccnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a mixture of 1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (2.72 g) and 1-methyl-2-pyrrolidone (100 ml) was added sodium hydride (70% in oil, 0.40 g), and the mixture was stirred at room temperature for 1 hour. (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.51 g) was added thereto, and the mixture was stirred at 100° C. for 8 hours under an argon atmosphere. After cooling, the reaction solution was diluted with ethyl acetate (400 ml), and washed with water (100 ml), 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (50 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate to ethyl acetate/acetone=5/1) and recrystallized from ethyl acetate-diisopropyl ether to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound 11; 1.82 g) as a pale yellow crystalline powder.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)=O.[NH2:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][C:17]2[N:22]=[C:21]([Cl:23])[C:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:19]([N:29]([CH3:31])[CH3:30])[N:18]=2)=[CH:14][CH:13]=1>C1COCC1>[Cl:23][C:21]1[C:20]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:19]([N:29]([CH3:30])[CH3:31])[N:18]=[C:17]([CH2:16][C:15]2[CH:14]=[CH:13][C:12]([NH:11][CH3:1])=[CH:33][CH:32]=2)[N:22]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1N(C)C
Solvent: O=CO
Solvent: C1CCOC1
Product: CNc1ccc(Cc2nc(Cl)c(CC(=O)OC)c(N(C)C)n2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To acetic anhydride (0.48 mL, 5.13 mmol) at 0° C. under Ar atmosphere was added formic acid (0.24 mL, 6.31 mmol) dropwise followed by heating of the mixture at 60° C. for 2 hours. After cooling to room temperature, THF (1 mL) was added followed by a solution of methyl [2-(4-aminobenzyl)-4-chloro-6-(dimethylamino)pyrimidin-5-yl]acetate (0.660 g, 1.97 mmol) in THF (1 ml). This was then stirred for 3 hours and concentrated to dryness. The remaining residue was dissolved in THF and cooled to 0° C. followed by the dropwise addition of borane dimethyl sulfide complex until the vigorous effervescence ceased. The mixture was gently refluxed for 14 hours and then cooled to 0° C. Methanol was added and the mixture was stirred at room temperature for 1 hour followed by the addition of concentrated HCl to pH ˜5 and stirring was continued for another 30 minutes. The solvent was evaporated in vacuo, the remaining residue basified with water and 1N NaOH, and the aqueous layer was extracted with Et2O. The combined organic extracts was dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the crude product which was chromatographed onver silica gel eluting with 5% acetone in CH2Cl2 to give methyl {4-chloro-6-(dimethylamino)-2-[4-(methylamino)benzyl]pyrimidin-5-yl}acetate (0.260 g, 38% yield) as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:8][CH2:7][C@@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@H:21]([OH:23])[CH3:22])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl.C1(C)C=CC=CC=1>[OH:23][C@@H:21]([C:10]1[N:9]([C@@H:6]2[CH2:7][O:8][C@@H:3]([CH2:2][NH:1][C:32](=[O:33])[O:34][CH:35]([CH3:37])[CH3:36])[CH2:4][CH2:5]2)[C:13]2=[C:14]3[S:20][CH:19]=[CH:18][C:15]3=[N:16][CH:17]=[C:12]2[N:11]=1)[CH3:22]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)OC1
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)NC[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
To a solution of (1R)-1-{1-[(3S,6R)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol (11 mg, 0.032 mmol) and triethylamine (22 μL, 0.16 mmol) in methylene chloride (1 mL) was added 1.0 M isopropyl chloroformate in toluene (39 μL). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (0.9 mg, 7%). LCMS calculated for C20H27N4O4S (M+H)+: m/z=419.2. Found: 419.0.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C@H:5]1[O:15][CH3:16])=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C@H:5]1[O:15][CH3:16]
Reactant: [H][H]
Reactant: CCOC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](OC)C1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CC[C@@H](N)[C@H](OC)C1
Yield: 97.4 %

Procedure:
A mixture of 15.6 parts of ethyl trans-4-azido-3-methoxy-1-piperidinecarboxylate and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated in vacuo, yielding 13.8 parts (97.4%) of ethyl trans-4-amino-3-methoxy-1-piperidinecarboxylate as a residue (interm. 5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[C:7](=[O:20])[C:6]2=[O:21].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7](=[O:20])[C:6]2=[O:21]
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 2-(5-methoxy-2,3-dioxoindolin-1-yl)acetate (0.65 g, 2.231 mmol) in DCM (20 ml), TFA (2.58 ml, 33.5 mmol) was added. The reaction was stirred at room temperature for 72 hours, then the solvent was evaporated to dryness affording 2-(5-methoxy-2,3-dioxoindolin-1-yl)acetic acid that was used in the next step without further purification (0.48 g, 2.041 mmol, 91% yield). MS/ESI+ 235.9 [MH]+
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:37][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]5[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH2:24]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:38][CH3:39].[ClH:40]>O1CCOCC1>[ClH:40].[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:37][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]5[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:38][CH3:39]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCC(NC(=O)OC(C)(C)C)CC4)ccnc3[nH]1)cn2C
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCC(N)CC4)ccnc3[nH]1)cn2C

Procedure:
The product is prepared by following the procedure described in example 51, starting with 0.120 g of tert-butyl (4-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}cyclohexyl)-carbamate instead of the tert-butyl (2-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}ethyl)carbamate used in example 51 and 2 cm3 of 5N hydrochloric acid in dioxane. 0.133 g of N-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]cyclohexane-1,4-diamine hydrochloride is obtained with the following characteristics:
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])[C:8]([Cl:22])=[N:7][C:6]=2[NH:5][C:3]1=[O:4].[C:23]1(OB(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])[C:8]([Cl:22])=[N:7][C:6]=2[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]1=[O:4]
Reactant: OB(O)Oc1ccccc1
Reactant: Cn1c(=O)[nH]c2nc(Cl)n(Cc3ccccc3C#N)c2c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2C#N)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 829 mg of 1-methyl-7-(2-cyano-benzyl)-8-chloro-xanthine, 640 mg of phenylboric acid, 509 mg of anhydrous copper acetate and 0.43 ml of pyridine in 20 ml methylene chloride is stirred for four days at ambient temperature in the presence of 100 mg of 4 Å molecular sieves. Then another 320 mg of phenylboric acid are added and the reaction mixture is stirred for another day at ambient temperature. For working up the mixture is filtered through talc and washed with ethyl acetate. The filtrate is evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate (7:3 to 1:1) as eluant.
Reaction SMILES: N1C=CC=C(CN)C=1.[S:9]1[C:13]([CH2:14][NH2:15])=[CH:12][N:11]=[CH:10]1.[F:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][N:22]2[C@@H:26]([CH3:27])[CH2:25][N:24]([C:28]3[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:23]2=[O:37])=[CH:19][CH:18]=1.FC1C=CC(CN2[C@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1>>[F:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][N:22]2[C@H:26]([CH3:27])[CH2:25][N:24]([C:28]3[S:29][C:30]([C:34]([NH:15][CH2:14][C:13]4[S:9][CH:10]=[N:11][CH:12]=4)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:23]2=[O:37])=[CH:19][CH:18]=1
Reactant: NCc1cncs1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cncs1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with thiazol-5-ylmethanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid the title compound was obtained as a white solid: mp 66-69° C. (hexane); 1H NMR (300 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.62 (t, J=5.7 Hz, 1H), 7.75 (s, 1H), 7.36-7.31 (m, 2H), 7.17-7.12 (m, 2H), 4.58-4.53 (m, 3H), 4.26 (d, J=15.6 Hz, 1H), 4.15 (t, J=9.6 Hz, 1H), 3.74-3.67 (m, 1H), 3.51 (dd, J=10.1, 6.8 Hz, 1H), 2.43 (s, 3H), 1.22 (d, J=6.1 Hz, 3H); MS (ES+) m/z 445.6 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH:3]=1.C(N(CC)CC)C.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(#N)C>[CH3:1][C:2]1[S:6]/[C:5](=[N:7]\[C:35]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:36])/[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=3[CH:9]=2)[CH:3]=1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)c(=N)s1
Reactant: O=C(Cl)N1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N2CCCCC2)s1
Temperature: 65 °C

Procedure:
The imine (Example 26A, 30 mg, 0.09 mmol) was dissolved in acetonitrile (1.5 mL). Triethylamine (19 μl, 0.18 mmol) was added followed by the 1-piperidinecarbonyl chloride (0.11 mmol). The reaction was heated at 65° C. overnight. The reaction mixture was cooled down and passed through a Si-amine cartridge (1 g, 1.6 mmol/g) to remove the excess carbamyl chloride eluting with additional acetonitrile. The resulting solution was dried and purified by reverse phase HPLC to supply the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (4 H), 1.53 (2 H), 2.20 (3 H), 3.43 (4 H), 7.24 (1 H), 7.63 (2 H), 7.83 (1 H); MS (ESI) m/z 432.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH:5]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]2[C:22](=[O:30])[N:23]([CH3:29])[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=2)[CH:18]=[C:17](Br)[CH:16]=1)[CH3:7])[CH3:2].[C:47]1(B(O)O)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH2:1]([O:3][C:4](=[O:46])[CH:5]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:18]=[C:19]([C:21]2[C:22](=[O:30])[N:23]([CH3:29])[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=2)[CH:20]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CCc1ccccc1OC(C(=O)OCC)C(C)CCCCCCOc1cc(Br)cc(-c2cn(C)c(=O)n(C)c2=O)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)CCc1ccccc1OC(C(=O)OCC)C(C)CCCCCCOc1cc(-c2ccccc2)cc(-c2cn(C)c(=O)n(C)c2=O)c1
Yield: 28.6 %

Procedure:
A similar procedure as described in Example 1, step 2 was used, starting from 4-[3-{6-[3-bromo-5-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-phenoxy]-hexyl}-(2-(2-ethoxycarbonyl-ethyl)-phenoxy)-butyric acid ethyl ester (27 mg, 0.04 mmol) and phenylboronic acid (23 mg, 0.19 mmol) to obtain 4-[3-{6-[5-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-biphenyl-3-yloxy]-hexyl}-(2-(2-ethoxycarbonyl-ethyl)-phenoxy)-butyric acid ethyl ester (8 mg, 30%) as a light yellow oil: ES(+)-LRMS m/e calculated for C41H50N2O8 (M+H)+ 699.6, found 699.4.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=2)[C:4](=[O:14])[CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C1C(=O)C(Cl)=C(Cl)[C:36](=[O:37])[C:35]=1C#N)#N>C(OC(C)C)(=O)C>[C:36]([O:14][C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH:11]=[C:2]([CH3:1])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:37])[CH3:35]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: COc1ccc2c(c1)CC(C)C(c1ccccc1)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)C
Product: COc1ccc2c(OC(C)=O)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A round-bottomed flask was charged with 3-methyl-6-(methyloxy)-2-phenyl-3,4-dihydro-1(2H)-naphthalenone (5) (3.8 g, 14.3 mmol), Isopropyl acetate (70 mL), and p-toluene sulfonic acid (1.4 g, 7.14 mmol). The reaction mixture was refluxed for 16 h under N2. Reaction mixture was cooled to room temperature and DDQ (9.74 g, 43 mmol) was introduced to the reaction mixture and refluxed for an additional 3 h. Reaction mixture was concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 column chromatography using hexanes:EtOAc (19:1 to 9:1) as an eluent to afford 4.10 g (94%) of the title compound (6). 1H NMR (400 MHz, CDCl3): δ 7.64 (d, J=12.0 Hz, 1H), 7.55 (br s, 1H), 7.43 and 7.39 (dd, J1=16.0 Hz, J2=8.0 Hz, 2H), 7.38 and 7.34 (m, 1H), 7.26-7.24 (m, 2H), 7.14-7.11 (m, 2H), 3.92 (s, 3H), 2.22 (s, 3H), 2.00 (s, 3H).