Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)C(=O)NNc1ccc(F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1nnc2ccc(F)cn12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 73.5 %

Procedure:
A solution of Example 1 step c (0.41 g, 2.08 mmol), triphenylphosphine (763 mg, 2.91 mmol) and triethylamine (0.87 mL, 6.24 mmol) in THF (5 mL) at 0° C. was treated with 1,2-hexachloroethane (690 mg, 2.91 mmol). The reaction mixture was stirred at 0° C. for 40 min then at RT for 20 min, quenched with water, extracted twice with EtOAc, dried (Na2SO4), evaporated and purified twice by FCC (cyclohexane/EtOAc 1/0 to 1/1) to afford the title compound (274 mg, contaminated with 20% PPh3O, 58%) as a white solid. LCMS (method 1): Rt 2.58 min, m/z 180 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[CH:18][C:19]([O:21][CH3:22])=[O:20])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:4]=2[CH:3]=1>C(O)C.[Pd]>[NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:4]=2[CH:3]=1
Reactant: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)Cc2cc(N)ccc21
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)Cc2cc(N)ccc21

Procedure:
To a stirring solution of methyl 2-[8-amino-2-[(tert-butyl)oxycarbonyl]-1H,3H,4H-benzo[e]azepin-5-ylidene}acetate in 25 ml of ethanol at room temperature was added 10% Pd/C(0.01M). The reaction was stirred under hydrogenation conditions at ballon pressure. After stirring for 4 hr, the reaction mixture was filtered through celite. The reaction solvent was removed by rotary evaporation. The residue was purified by flash chromatography (50% EtOAc/Hexane). EI-MS m/z 335 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:36](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([N:30]6[CH2:35][CH2:34][O:33][CH2:32][CH2:31]6)=[CH:26][CH:25]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:47][CH3:48].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:36][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][C:24]5[CH:25]=[CH:26][C:27]([N:30]6[CH2:31][CH2:32][O:33][CH2:34][CH2:35]6)=[CH:28][CH:29]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:47][CH3:48]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNCc4ccc(N5CCOCC5)cc4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCc4ccc(N5CCOCC5)cc4)ccnc3[nH]1)cn2C
Yield: 56.4 %

Procedure:
The product is prepared by following the procedure described in example 34, stage (k), starting with 0.03 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(4-morpholin-4-yl-benzyl)amine instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34, stage (k) and 0.18 cm3 of 5N potassium hydroxide. 0.013 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(4-morpholin-4-yl-benzyl)amine is obtained with the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][CH3:21])=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][C:29]([C:31]2([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32]2)=[O:30])=[CH:25][C:24]=1[N:40]=[C:41]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][NH:28][C:29]([C:31]2([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32]2)=[O:30])=[CH:25][C:24]=1[NH:40][C:41]1[N:20]([CH3:21])[C:3]2[CH:4]=[C:5]([N:10]3[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:17])[F:18])[CH2:12][CH2:11]3)[C:6]([C:7]#[N:8])=[CH:9][C:2]=2[N:1]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C#N)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(C#N)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to Example 76 using 5-amino-4-(methylamino)-2-(4-trifluoromethyl-piperidin-1-yl)benzonitrile (179 mg, 0.60 mmol), N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (200 mg; 0.60 mmol), DIC (76 mg, 0.60 mmol) and DMF (4 mL).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.OC1C2N=NNC=2C=CC=1.Cl.C([O:28][C:29](=[O:49])[CH:30]([NH:42][C:43]([O:45][CH2:46][CH:47]=[CH2:48])=[O:44])[CH2:31][C:32]1[O:36][N:35]=[C:34]([CH:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)[CH:33]=1)C.C(N(CC)CC)C>CN(C)C=O.O>[CH2:46]([O:45][C:43]([NH:42][CH:30]([CH2:31][C:32]1[O:36][N:35]=[C:34]([CH:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH:33]=1)[C:29]([OH:49])=[O:28])=[O:44])[CH:47]=[CH2:48]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc([N+](=O)[O-])cc2)no1)C(=O)O
Reaction time: 0.5 h
Yield: 17.3 %

Procedure:
A dimethyl formamide (82 mL) solution of 4-nitrophenylacetic acid (1.61 g, 8.87 mmol) in dimethyl formamide (82 mL) was stirred with 4-hydroxybenzotriazole monohydrate (1.40 g, 10.4 mmol) for 10 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (1.86 g, 9.72 mmol) was added and the mixture was stirred until all 1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride had dissolved. To this solution, 2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride from Example 1C (3.16 g, 8.25 mmol) was added and the mixture stirred 30 minutes followed by addition of triethyl amine (1.26 mL, 9.04 mmol). After the reaction had stirred at room temperature over night it was poured into water and extracted with ethyl acetate three times. The combined extracts were washed with a saturated solution of sodium bicarbonate, water (2×) and brine. The organic portion was dried over magnesium sulfate and concentrated. The resulting residue was chromatographed on a Biotage Flash 40S column eluting with ethyl acetate/hexanes (5:1) to yield the title compound as a yellow oil (674 mg, 15%). MS (Cl) m/z 501.3 (M+1). Additionally, starting material 2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester was recovered (2.15 g, 75%). MS (Cl) m/z 338.1 (M+1)
Reaction SMILES: Cl[CH2:2][CH:3]=[O:4].[CH3:5][C:6]1[N:11]=[C:10]([NH:12][C:13](=[S:15])[S-:14])[CH:9]=[CH:8][CH:7]=1.C([NH+](CC)CC)C.C(O)C>O>[OH:4][CH:3]1[CH2:2][S:15][C:13](=[S:14])[N:12]1[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:5])[N:11]=1
Reactant: Cc1cccc(NC(=S)[S-])n1
Reactant: O=CCCl
Agent: CC[NH+](CC)CC
Solvent: CCO
Solvent: O
Product: Cc1cccc(N2C(=S)SCC2O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A 50% aqueous solution of chloroacetaldehyde (28.4 g) is added, at between 20° and 30° C., to a solution of triethylammonium 6-methylpyrid-2-yldithiocarbamate (51.5 g) in distilled water (225 cc). The reaction mixture is stirred for 2 hours at 25° C. The crude product is filtered off, washed five times with distilled water (total 125 cc) and dried in air. The product obtained (37.0 g; m.p. 128° C.) is dissolved in boiling ethanol (250 cc). After filtering the boiling solution and cooling the filtrate for 2 hours at 2° C., the resulting crystals are filtered off, washed three times with ice-cooled ethanol (total 30 cc) and dried under reduced pressure (0.2 mm Hg) at 40° C. 4-Hydroxy-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (29.8 g), melting at 128° C., is thus obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:21]=[C:20]4[C:14]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)=[N:13]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]1(=O)[CH2:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:22]1([N:17]2[CH2:18][CH2:19][C:20]3=[CH:21][N:12]([C:9]4[CH:10]=[CH:11][C:6]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[CH:7][CH:8]=4)[N:13]=[C:14]3[CH2:15][CH2:16]2)[CH2:25][CH2:24][CH2:23]1
Reactant: O=C1CCC1
Reactant: c1cc(-n2cc3c(n2)CCNCC3)ccc1N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: c1cc(-n2cc3c(n2)CCN(C2CCC2)CC3)ccc1N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[4-(1-pyrrolidinyl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 45) (25 mg, 0.09 mmol) in dichloromethane (4 ml) was added cyclobutanone (30 μl, 0.45 mmol) followed by acetic acid (3 drops). The mixture was stirred at room temperature for 30 min, then treated with sodium triacetoxyborohydride (95 mg, 0.45 mmol). The mixture was stirred at room temperature for 4 hours, then it was diluted with methanol and purified by SCX cartridge to afford the title compound (E41). MS (ES+) m/e 337 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:23]([O-])=O)(=[O:3])[CH3:2].[H][H]>CO.COCCO.[Ni]>[C:1]([NH:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:14])=[CH:9][C:8]=1[NH2:23])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: COCCO
Solvent: CO
Product: CC(=O)NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1N

Procedure:
48 g of 2-(3-acetylureido)-5-phenoxysulfonylnitrobenzene in 300 ml of methanol and 300 ml of 2-methoxyethanol are hydrogenated under normal pressure with a catalytic amount of Raney nickel. After hydrogen uptake is complete, the catalyst is filtered off with suction, washed with dimethylformamide and the solution is evaporated under reduced pressure. The residue is stirred with hot methanol, and the solid is filtered off cold under suction and washed with methanol and diisopropyl ether, melting point 202° C., decomposition.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[C:18]1([C:9]2[C:8]3[C:17]4=[C:16]5[C:5](=[CH:6][CH:7]=3)[CH:4]=[CH:3][CH:2]=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: c1ccc(-c2ccc3ccc4cccc5ccc2c3c45)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
A mixed solution of 9.4 g of 1-bromopyrene, 4.5 g of phenylboronic acid, 13 g of cesium carbonate, 348 mg of (tri-tert-butylphosphine) tetrafluoroborate, 575 mg of bis(dibenzylideneacetone)palladium(0), and 33 ml of 1,4-dioxane was heated and stirred at 100° C. for 3 hours under a nitrogen stream. The solution was cooled to room temperature and then filtered through celite. The filtrate was evaporated, and the resulting concentrate was purified by silica gel column chromatography and dried under vacuum to give 7.8 g of 1-phenylpyrene.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[N:6]3[C:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)=[CH:9][C:8]([C:14]([OH:16])=O)=[N:7]3.[CH:19]([NH:22][CH2:23][CH2:24][OH:25])([CH3:21])[CH3:20].C(N(CC)CC)C>[Pd]>[OH:25][CH2:24][CH2:23][N:22]([CH:19]([CH3:21])[CH3:20])[C:14]([C:8]1[CH:9]=[C:10]2[N:6]([C:5]3[CH:17]=[CH:18][CH:2]=[CH:3][C:4]=3[O:13][CH2:12][CH2:11]2)[N:7]=1)=[O:16]
Reactant: CC(C)NCCO
Reactant: O=C(O)c1cc2n(n1)-c1ccc(Br)cc1OCC2
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CC(C)N(CCO)C(=O)c1cc2n(n1)-c1ccccc1OCC2
Reaction time: 2.75 h
Yield: 68 %

Procedure:
Following the procedure for 116, 8-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid was reacted with 2-isopropylamino-ethanol. The intermediate formed (145 mg, 0.37 mmol) was dissolved in IMS (10 mL) and triethylamine (50 L, 0.37 mmol) then 10% Pd/C (20 mg) added before the reaction mixture stirred under hydrogen (1 atmosphere) for 2.75 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resultant residue was partitioned between DCM and water, the aqueous layer was isolated and extracted with DCM. The combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was dissolved in diethyl ether and the solution washed with water, dried (Na2SO4), filtered and then concentrated in vacuo to give 140 (79 mg, 68%). 1H NMR (DMSO-d6, 400 MHz): δ 7.83 (dd, J=8.0, 1.6 Hz, 1 H); 7.30 (td, J=7.6, 1.8 Hz, 1 H); 7.26-7.16 (m, 2 H); 6.54 (s, 1 H); 4.67-4.53 (m, 1 H); 4.46 (t, J=6.0 Hz, 2 H); 4.35-4.27 (m, 1 H); 3.64-3.56 (m, 2 H); 3.55-3.46 (m, 2 H); 3.13 (t, J=6.0 Hz, 2 H); 1.22 (d, J=6.8 Hz, 6 H). LCMS: RT=9.00 min, M+H+=316
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[C:16]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:15][C:14]([Cl:31])=[CH:13][N:12]=2)[CH:10]=1)=O)C.[OH-].[Na+].[CH3:34][NH:35][CH3:36].C(N(CC)CC)C>C(O)(=O)C.C1COCC1>[CH3:34][N:35]([CH3:36])[C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[C:16]([NH:17][S:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:25][CH:26]=3)(=[O:20])=[O:19])=[CH:15][C:14]([Cl:31])=[CH:13][N:12]=2)[CH:10]=1)=[O:3]
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)C(=O)c1cnn(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A 25 mL scintillation vial was charged with 1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (synthesized according to general procedure D, 93 mg, 0.2 mmol), NaOH (2 mL, 1.0 M solution in water), and THF (3 mL). The vial was sealed and stirred at 80° C. for 16 hours. The reaction solution was subsequently neutralized to pH=5 with glacial acetic acid. The mixture was extracted with ethyl acetate (2×10 mL) and the combined organics were concentrated in vacuo. The crude product was subsequently dissolved in 2 mL of THF in a 25 mL scintillation vial. To the resultant solution was added with dimethylamine (0.2 mL, 2.0 M in THF), 1-propanephosphonic anhydride solution (184 mg, 50% solution in ethyl acetate), and triethylamine (41 mg, 0.4 mmol). The vial was sealed and stirred at ambient temperature for 1 hour. The volatiles were then evacuated in vacuo and the residue was purified via preparative HPLC to afford 1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazole-4-carboxylic acid dimethylamide as a white powder: MS (ES) M+H expected 462.1, found 462.0.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH:11]=[CH:10][CH:9]=[C:8]3[CH2:7]1)C.[OH-].[K+].O>CO>[CH:6]1([CH2:5][C:4]([OH:18])=[O:3])[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH:11]=[CH:10][CH:9]=[C:8]3[CH2:7]1
Reactant: CCOC(=O)CC1Cc2cccc3cccc1c23
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC1Cc2cccc3cccc1c23

Procedure:
The ester obtained in Step C (1.9 g, 7.91.10−3 mol) is heated at reflux in the presence of potassium hydroxide (2.34 g, 4.17.10−2 mol, 5.3 eq.), water (16 ml) and methanol (16 ml) for one night. After evaporating off the solvent, the residue is taken up in water and extracted twice with ether. The basic aqueous phase is acidified using concentrated HCl in the cold state. The acid is extracted with ethyl acetate and dried over MgSO4. After evaporating off the solvent under reduced pressure, the title compound is obtained in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:34]2[S:38][C:37]([C:39]3([O:43]CC4C=CC(OC)=CC=4)[CH2:42][O:41][CH2:40]3)=[N:36][CH:35]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:23]=[CH:22][C:14]([CH2:15][N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[CH:13][CH:12]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([C:34]2[S:38][C:37]([C:39]3([OH:43])[CH2:40][O:41][CH2:42]3)=[N:36][CH:35]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH2:15][N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)=[CH:22][CH:23]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(COC2(c3ncc(-c4c(Cl)cnc5c4cc(-c4ccc(CN6CCOCC6)cc4)n5S(=O)(=O)c4ccc(C)cc4)s3)COC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc(CN4CCOCC4)cc3)cc3c(-c4cnc(C5(O)COC5)s4)c(Cl)cnc32)cc1
Reaction time: 0.5 h

Procedure:
To an ambient solution of 4-(4-(5-chloro-4-(2-(3-(4-methoxybenzyloxy)oxetan-3-yl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)benzyl)morpholine (Example 11H) (130 mg, 0.172 mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (2.5 mL, 32.4 mmol). The reaction was stirred for 0.5 hours and was then concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (5 mL) and saturated aqueous bicarbonate solution (1 mL). The layers were separated, and the organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 10% methanol in dichloromethane, to give the title compound. MS ESI(+) m/z 637.1 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)([CH2:14][OH:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>ClCCl>[ClH:28].[F:26][C:24]([F:25])([F:27])[O:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][C:11]1([CH2:14][OH:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(Cc2cccc(OC(F)(F)F)c2)CC1
Agent: Cl
Solvent: ClCCl
Product: OCC1(Cc2cccc(OC(F)(F)F)c2)CCNCC1
Reaction time: 2.5 h

Procedure:
A solution of N-tert-butoxycarbonyl-4-(3-trifluoromethoxy-benzyl)-4-hydroxymethylpiperidine (2.9 g) in dichloromethane (100 mL) at 0° C. was saturated with hydrogen chloride gas. The resultant solution was sealed with a rubber septum and stirred at room temp. for 2.5 h. The product solution was concentrated under vacuum to provide the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:38][CH2:39][CH2:40][CH3:41])[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1>>[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:38][CH2:39][CH2:40][CH3:41])[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:2](=[O:3])[O:4][CH2:5][CH:6]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 70.8 %

Procedure:
Using the general method of Example 55, 9-fluorenylmethyl chloroformate (0.085 g, 0.33 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.105 g, 0.33 mmol) to provide 0.125 g of 9H-9-fluorenylmethyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a white powder. Analysis: Calculated for C32H34N6O2+1/4 H2O: %C, 71.29; %H, 6.45; %N, 15.59; Found: %C, 70.99; %H, 6.35; %N, 15.55.
Reaction SMILES: N[C:2]1[C:3]2[C:29]([CH3:31])([CH3:30])[C:28](=[O:32])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([CH3:17])=[N:14][CH:15]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:9]=2)[N:7]=1.[I:33]CI.N(OCCC(C)C)=O.C(N(CC)CC)C>C(#N)C>[F:26][C:20]1[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:10]1[C:11]2=[N:12][C:13]([CH3:17])=[N:14][CH:15]=[C:16]2[C:8]([C:6]2[N:7]=[C:2]([I:33])[C:3]3[C:29]([CH3:31])([CH3:30])[C:28](=[O:32])[NH:27][C:4]=3[N:5]=2)=[N:9]1
Reactant: Cc1ncc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C)nn(Cc3cccc(F)c3F)c2n1
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ncc2c(-c3nc(I)c4c(n3)NC(=O)C4(C)C)nn(Cc3cccc(F)c3F)c2n1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
150 mg (0.34 mmol) of 4-amino-2-[1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one were admixed with 6.650 g (19.86 mmol) of diiodomethane and 402 mg (3.44 mmol) of isopentyl nitrite. The mixture was stirred at 85° C. for 8 h. 70 mg (0.69 mmol) of triethylamine were added and the mixture was again boiled under reflux at 85° C. After cooling, the mixture was diluted with acetonitrile and purified by means of preparative HPLC (eluent: acetonitrile/water with, gradient 30:70→95:5). 44 mg (purity 67%, 16% of theory) of the target compound were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19].O1CCOCC1>CO>[ClH:19].[O:18]=[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][CH2:16][OH:17]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCO)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(CCO)N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperazine, 3-hydroxypropionic acid, 1-hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and DMF was stirred for 24 hours at room temperature to give 3-(4-tert-utoxycarbonylpiperazine-1-yl)-3-oxopropane-1-ol. A mixture of the obtained 3-(4-tert-butoxycarbonylpiperazine-1-yl)-3-oxopropane-1-ol, 4M HCl-dioxane solution and MeOH was stirred for 16 hours at room temperature to give 3-oxo-3-piperazine-1-ylpropane-1-ol hydrochloride.
Reaction SMILES: [CH:1]1([C:6]([OH:27])([C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:7][C:8]2[O:13]C(C)(C)O[C:10](=[O:16])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([C:6]2([C:17]#[C:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[O:27][C:10](=[O:16])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1
Solvent: CO
Product: COc1ccc(C#CC2(C3CCCC3)CC(=O)CC(=O)O2)cc1
Yield: 28 %

Procedure:
A solution of 6-[2-cyclopentyl-2-hydroxy-4-(4-methoxy-phenyl)-but-3-ynyl]-2,2-dimethyl-[1,3]dioxin-4-one (55 mg, 0.1485 mmol), 1NaOH n(150 μL, 0.1485 mmol), and MeOH (1.5 mL), was stirred at room temperature for 2 hours, at which time HPLC indicated that all starting material had been consumed. The reaction was quenched with 0.5 N citric acid, and extracted with ethylacetate. The organic layer was dried with MgSO4, concentrated and purified by preparative HPLC, giving 13 mg of the product (24% yield). 1H NMR (CDCl3): δ 1.73 (m, 4H), 2.23 (pentet, 1H, J=8.1 Hz), 2.85 (d, 1H, J=16.3 Hz), 2.95 (d, 1H, J=16.5 Hz), 3.45 (d, 1H, J=21.5 Hz), 3.85 (s, 3H), 3.98 (d, 1H, J=22.0 Hz), 6.84 (d, 2H, J=8.7 Hz), 7.32 (d, 2H, J=8.1 Hz); ESIMS (M+Na+): 335.1.