Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18]>C(O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([CH2:13][NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CNCC(O)CO
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(CNCC(O)CO)n1
Temperature: 0 °C
Yield: 87.1 %

Procedure:
4 g (0.0219 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 50 ml of ethanol and 4.15 ml (0.0438 mol) of 3-methylamino-1,2-dihydroxypropane are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 4.74 g of yellow powder are obtained, ie a yield of 87.1%.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH:21](I)[CH3:22].CN(C)C=O>C(OCC)(=O)C>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COCCOCCOC(C)I
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCCOCCN1C(=O)c2ccccc2C1=O
Reaction time: 3 h

Procedure:
1.3 g of potassium phthalimide, 2-methoxyethoxyethoxy-1-iodoethane and 5 ml of dimethylformamide were fed into a 100 ml short-neck flask provided with a reflux condenser. The resultant mixture was heated at 90° c. for 3 hours. 100 ml of ethyl acetate was added thereto and the resultant mixture was cooled to room temperature. White precipitates thus obtained were suction-filtered, and the filtrate was washed with 100 ml of water. The obtained ethyl acetate layer was dried over magnesium sulfate, and ethyl acetate was distilled off under reduced pressure to obtain the intended compound.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:16][S:17][C:18]1[N:19]=[CH:20][C:21]2[C:26](=O)[O:25]C(=O)[N:23]([CH:29]([CH3:31])[CH3:30])[C:22]=2[N:32]=1.Cl>O>[CH2:10]([O:9][C:7]([C:6]1[C:5](=[O:13])[N:23]([CH:29]([CH3:30])[CH3:31])[C:22]2[N:32]=[C:18]([S:17][CH3:16])[N:19]=[CH:20][C:21]=2[C:26]=1[OH:25])=[O:8])[CH3:11]
Reactant: CSc1ncc2c(=O)oc(=O)n(C(C)C)c2n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(O)c2cnc(SC)nc2n(C(C)C)c1=O

Procedure:
To a solution of sodium ethoxide (0.9 g. 0.039 g. atom of sodium in 75 ml. of ethanol) was added 6.24 g. (0.03 mole) of diethyl malonate. The ethanol was removed in a rotary evaporator. To the residue was added 100 ml. of dimethyl formamide followed by 3.3 g. (0.013 mole) of 7-methylthio-1-isopropyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione. The reaction mixture was heated under reflux for 1 hour, cooled in ice and poured into 400 ml. of water. The solution was acidified with conc. hydrochloric acid and the resulting product was collected by suction filtration. Recrystallization from ethanol gave 2 g. of product--m.p. 138°-140° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:23])[C:7]=2[N:6]=[C:5]1[CH2:24][O:25][CH2:26][CH3:27].[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[NH2:23][C:8]1[C:7]2[N:6]=[C:5]([CH2:24][O:25][CH2:26][CH3:27])[N:4]([CH2:3][CH2:2][NH:1][C:32]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:33])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)N=C=O
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCN
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)NC(C)C
Yield: 28.5 %

Procedure:
A solution of 1-(2-aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.50 g, 6.90 mmol) in chloroform (50 mL) was treated with isopropyl isocyanate (0.65 mL, 6.9 mmol) according to the method described in Examples 377-379. The crude product was purified by column chromatography on silica gel (eluting with 94:6 chloroform:methanol) followed by trituration with acetonitrile (15 mL/g) at 95° C. The mixture was cooled in an ice bath, isolated by filtration, and dried for one hour in a vacuum oven at 100° C. to provide 0.88 g of N-{2-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-N′-(1-methylethyl)urea as a white solid, mp 194-196° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)(=O)C>[C:14]1([C:3]2[C:4]([CH3:13])=[N:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]=2[NH2:1])[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: O=C1CCCCC1
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Solvent: CC(=O)O
Product: Cc1nn(-c2ccccc2)c(N)c1C1=CCCCC1
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A solution of 5-amino-3-methyl-1-phenylpyrazole (8.66 g, 50 mmol) in acetic acid (70 mL) was treated with cyclohexanone (10.6 mL, 100 mmol) at ambient temperature for 40 hours. The volatiles were removed and the residue diluted with water and 10% sodium hydroxide added until the pH=12. The mixture was stirred with 10 mL of hexane for 30 minutes and the solid collected by filtration, washed with water and hexane and dried to give 9.43 g (74%) of the title compound. MS (DCI): m/z 254 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([Cl:57])[CH:51]=1)[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:23]=[CH:22][C:21]([C:24](=[O:48])[NH:25][S:26]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[C:32]([O:39][CH2:40][CH2:41][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)[CH:33]=[CH:34][CH:35]=4)[CH:30]=3)(=[O:28])=[O:27])=[CH:20][C:16]=2[C:17](O)=[O:18])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[N:58]([CH2:61][C@@H:62]1[CH2:71][C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH2:64][NH:63]1)=[N+:59]=[N-:60]>>[N:58]([CH2:61][C@@H:62]1[CH2:71][C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH2:64][N:63]1[C:17]([C:16]1[CH:20]=[C:21]([C:24](=[O:48])[NH:25][S:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[C:32]([O:39][CH2:40][CH2:41][N:42]4[CH2:43][CH2:44][O:45][CH2:46][CH2:47]4)[CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:28])=[O:27])[CH:22]=[CH:23][C:15]=1[N:10]1[C:11]([CH3:14])=[C:12]([Cl:13])[C:8]([C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:49][C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([Cl:57])[CH:51]=2)=[O:7])=[N:9]1)=[O:18])=[N+:59]=[N-:60]
Reactant: [N-]=[N+]=NC[C@@H]1Cc2ccccc2CN1
Reactant: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])c(C)c1Cl
Yield: 77.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 91, 2-(3-(butyl(3,4-dichlorobenzyl)carbamoyl)-4-chloro-5-methyl-1H-pyrazol-1-yl)-5-(8-(2-morpholinoethoxy)naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 186B, 17 mg, 0.020 mmol) and (S)-3-(azidomethyl)-1,2,3,4-tetrahydroisoquinoline (Intermediate 92A, 15 mg, 0.079 mmol) were converted to the title compound (16 mg, 79%). MS(ESI+) m/z 1028.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:30])[C@@H:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:28]([O:27][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[CH:11][CH:12]=1)[C:4]([OH:30])=[O:3])[CH3:29]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2ccc3ccccc3c2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCO[C@@H](Cc1ccc(OC/C=C/c2ccc3ccccc3c2)cc1)C(=O)O
Temperature: 35 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
(E)-(S)-2-Ethoxy-3-[4-(3-naphthalen-2-yl-allyloxy)-phenyl]-propionic acid ethyl ester (example 23) (170 mg, 0.42 mmol) was dissolved in ethanol (20 mL) at 35° C. and sodium hydroxide (1N, 2.1 mL, 2.1 mmol) added. The mixture was stirred at 35° C. for 1 h, the ethanol evaporated in vacuo and the mixture acidified to pH 1 with 1N hydrochloric acid. The product was isolated by extraction with ethyl acetate (30 mL×2). The combined organic phases were dried (MgSO4), filtered and evaporated to give 155 mg (98%) of the title compound as crystals.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=2[N+:14]([O-])=O)[CH2:3][CH2:2]1>CCOC(C)=O>[NH2:14][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:6]=1[NH:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)[C:10]#[N:11]
Reactant: N#Cc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NCC2CC2)c(N)c1
Reaction time: 2 h
Yield: 94.5 %

Procedure:
Following the general procedure 2C, crude 4-[(cyclopropylmethyl)-amino]-3-nitrobenzonitrile (920 mg, 4.24 mmol) was hydrogenated for 2 h (35 psi) in 40 mL of EtOAc to yield 750 mg crude product (95%) and was used for the next step without further purification. MS (ESI) (M+H)+=188.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl>C(Cl)Cl.O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2nc(CC3CCNCC3)ccc2n1

Procedure:
tert-butyl 4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidine-1-carboxylate from Example 137 (0.33 g) in DCM (5 mL) was treated with 4N HCl in dioxane (0.9 mL) for 30 minutes at room temperature. The reaction mixture was concentrated to dryness to afford quantitative yield of 4-(2-chloro-6-(piperidin-4-ylmethyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Gd+3:5].[CH3:6][CH:7]([CH3:9])[O-:8].[CH3:10][CH:11]([CH3:13])[O-:12].[CH3:14][O:15][CH2:16][CH2:17]O>>[CH3:1][CH:2]([CH3:4])[O-:3].[Gd+3:5].[CH3:6][CH:7]([CH3:9])[O-:8].[CH3:10][CH:11]([CH3:13])[O-:12].[CH3:14][O:15][CH:16]([CH3:17])[O-:3].[Gd+3:5].[CH3:14][O:15][CH:16]([CH3:17])[O-:3].[CH3:14][O:15][CH:16]([CH3:17])[O-:3]
Reactant: COCCO
Agent: CC(C)[O-]
Agent: [Gd+3]
Product: COC(C)[O-]

Procedure:
Gadolinium isopropoxide was synthesized using the method of Brown et al. The Gd2O3 precursor solution was prepared by reacting 4.85 g (15 mmole) of gadolinium isopropoxide with 50 ml of 2-methoxyethanol under an inert atmosphere. After refluxing for approximately 1 hour, two-thirds of the solution (isopropanol and 2-methoxyethanol) was removed by distillation. The flask was allowed to cool, and 20 ml of 2-methoxyethanol was added. The flask was refluxed for 1 hour, and ⅔ of the solution was then removed by distillation. This process of dilution, reflux, and distillation was repeated for a total of three cycles to ensure the complete exchange of the methoxyethoxide ligand for the isopropoxide ligand. It was estimated that this occurs when the boiling point of the solution reaches 124° C. The final concentration of the solution was adjusted to obtain a 0.5 M solution of gadolinium methoxyethoxide in 2-methoxyethanol. A partially hydrolyzed solution suitable for spin coating or dip-coating was prepared by reacting 1 part of a 1.0 molar solution of water in 2-methoxyethanol with 4 parts of the 0.5 M gadolinium methoxyethoxide solution.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[N:9]=[C:10]([C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)[C:3]=12.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].[OH-].[Na+]>CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][C:17]([OH:19])=[O:18])[N:9]=[C:10]([C:11]3[NH:15][CH:14]=[CH:13][N:12]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)Cn1nc(C2=NCCN2)c2c(N)ncnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-Butyl 2-(4-amino-3-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate (84 g, 0.265 mol) and DMSO (900 mL) in an ice water bath was added Dess-Martin periodinane (169.6 g, 0.4 mol) in portions while keeping the internal temperature below 25° C. The mixture was stirred for 2 h at room temperature and then poured into ice water (2 L) which contained 84 g of Na2S2O3. The mixture was adjusted to pH 12-14 with 3 N NaOH and filtered to give a solid, which was washed with water, re-suspended in ice-water (2 L), filtered, washed with water (500 mL), EtOAc (100 mL×2) and Et2O (100 mL×2), and dried in vacuo to give (2-(4-amino-3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetic acid tent-butyl ester (66.2 g, 80% yield). MS (ES) m/z 316.1 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[CH:29]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[CH:29]1([C:33]([N:25]([CH2:24][C:15]2[CH:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:14]=2[C:8]2[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:28])[CH:7]=2)[CH2:26][CH3:27])=[O:34])[CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CCC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CCC1

Procedure:
{2′-[(Cyclobutanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-206) was prepared using the procedures of Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclobutanecarbonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:37])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([N:29]3[CH2:34][C@@H:33]([CH3:35])[NH:32][CH2:31][C@@H:30]3[CH3:36])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:16]=2)[CH2:9][CH2:8]1)[CH3:2].[F:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH:43]=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:37])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([N:29]3[CH2:34][C@@H:33]([CH3:35])[N:32]([CH2:43][C:42]4[CH:45]=[CH:46][CH:47]=[C:40]([F:39])[CH:41]=4)[CH2:31][C@@H:30]3[CH3:36])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:16]=2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CCN1CCCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Reactant: O=Cc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)CCN1CCCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4cccc(F)c4)C[C@@H]3C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 3-(4-{3-[(R)-((2S,5R)-2,5-Dimethyl-piperazin-1-yl)-(3-hydroxy-methyl]-benzoyl}-[1,4]diazepan-1-yl)-propionic acid ethyl ester (288 mg; Example 11), 3-fluorobenzaldehyde (137 mg) and acetic acid (66 mg) in DMF (3 mL) was stirred under nitrogen at room temperature for 20 minutes, followed by the addition of Na(OAc)3BH (292 mg). The reaction was stirred under nitrogen at room temperature for overnight. The reaction was quenched by the addition of H2O (4 mL). The solution was neutralized by sat. NaHCO3 solution to pH≅7. The solution was extracted by EtOAc (5 mL×3). The combined organic layer was washed by water (5 mL×2) and brine (5 mL×1), dried by Na2SO4 and concentrated to give crude product (300 mg), which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16× (gradient: 100% CH2Cl2 to 10% MeOH in CH2Cl2) to give 3-(4-{3-[(R)-[(2S,5R)-4-(3-Fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-(3-hydroxy-phenyl)-methyl]-benzoyl}-[1,4]diazepan-1-yl)-propionic acid ethyl ester as white solid (120 mg; 35%). 1H NMR (300 MHz, CDCl3) δ 7.59-7.48 (m, 1H), 7.40-7.22 (m, 4H), 7.16-7.04 (m, 3H), 6.92 (m, 1H), 6.72 (m, 3H), 5.04 (bs, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.92 (m, 1H), 3.77 (m, 1H), 3.71 (m, 1H), 3.43 (m, 1H), 3.35 (m, 1H), 3.24 (m, 1H), 2.94-2.81 (m, 3H), 2.72-2.44 (m, 9H), 2.05 (m, 2H), 1.96 (m, 1H), 1.75 (bs, 1H), 1.26 (t, J=7.0 Hz, 3H), 1.06 (m, 6H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:32][NH:33]C(OC(C)(C)C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C>CO.Cl>[NH2:33][CH2:32][CH:31]([NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][N:27]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1ccccc1
Agent: Cl
Solvent: CO
Product: NCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(N)CC4)ncc23)n1)c1ccccc1

Procedure:
To a solution of (4-{3-[2-(2-tert-butoxycarbonylamino-1-phenyl-ethylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (35 mg, 0.05 mmol) in methanol (30 mL) was bubbled in HCl (gas) for 3 hours at room temperature. The mixture was then concentrated by evaporation to afford N-{3-[2-(2-amino-1-phenyl-ethylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 23 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C([N:14]=C=NCCCN(C)C)C.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1c(Cl)cccc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccc(Cl)c1N
Reaction time: 6 h
Yield: 50.4 %

Procedure:
To 2-amino-3-chlorobenzoic acid (1.72 g, 10 mmol) in DMF (5 mL) were added hydroxybenzatriazole (2.0 g, 13 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.3 g, 12 mmol), ammonium chloride (2.3 g, 42 mmol), and DIEA (7.5 ml, 42 mmol). The mixture was purged with nitrogen and was stirred for 6 h. The mixture was then poured into water and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (2×20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (10 mL) resulting in a precipitate that was collected by filtration to afford 2-amino-3-chlorobenzamide (860 mg). LCMS (ESI) m/z 171 (M+H)+.
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([C:18]([C:23]2[N:24]=[CH:25][N:26]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]=2)([OH:22])[CH:19]([CH3:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1>>[CH3:20][CH:19]([CH3:21])[C:18]([C:14]1[CH:13]=[C:12]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1)([C:23]1[N:24]=[CH:25][N:26]([C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=1)[OH:22]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: Cc1ccc(-c2cccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)c2)cc1
Yield: 72.3 %

Procedure:
By the reaction in the same manner as in Example 1-(i) using p-tolylboronic acid (0.45 g) and 1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.03 g), the title compound (0.76 g) was obtained as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:15][CH2:16][O:17][C:18](Cl)=[O:19].Cl>>[CH2:16]([O:17][C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)=[O:19])[CH3:15]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)Oc1ccc(/C=C/C(=O)O)cc1
Temperature: 10 °C
Yield: 83.6 %

Procedure:
67 g (400 mmol) of (2E)-3-(4-hydroxyphenyl)prop-2-enoic acid is added to a mixture of 57.4 g (880 mmol) of potassium hydroxide in 600 ml at 0° C. 46.6 mL (480 mmol) of ethyl chloridocarbonate are added dropwise so that the temperature is maintained to 10° C. The reaction mixture is subsequently allowed to react for 2 hours at 25° C. and then acidified to pH=1 with 200 mL of a 25% HCl solution- The precipitate is filtered off and washed with 500 mL of water. The residue is crystallized in 2 L of toluene and dried under vacuum to yield 79 g (74%) of pure (2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}prop-2-enoic acid as a white powder.
Reaction SMILES: [CH2:1]1[C@@:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=3)[C:17]2=[O:27])=[CH:12][CH:11]=1.[CH3:28][C:29]1([CH3:32])[CH2:31][O:30]1>>[OH:26][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:27])[N:16]([C:13]1[CH:14]=[CH:15][C:10]([N:2]3[CH2:3][CH2:4][C@:5]4([CH2:9][CH2:8][N:7]([CH2:28][C:29]([OH:30])([CH3:32])[CH3:31])[CH2:6]4)[CH2:1]3)=[CH:11][CH:12]=1)[CH:25]=[CH:24]2
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@]3(CCNC3)C2)cc1
Reactant: CC1(C)CO1
Product: CC(C)(O)CN1CC[C@]2(CCN(c3ccc(-n4ccc5cc(O)ccc5c4=O)cc3)C2)C1

Procedure:
According to Method U, 2-[(S)-4-(2,7-diaza-spiro[4.4]non-2-yl)-phenyl]-6-hydroxy-2H-isoquinolin-1-one was reacted with 2,2-dimethyl-oxirane. In this way the product was obtained with molecular weight 433.56 (C26H31N3O3); MS (ESI): 434 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1[CH:12]=[C:11]2[C:13]([O:15][C:16]([C:18]3=[CH:19][CH:20]=[CH:21][C:9](=[C:10]23)[CH:8]=1)=O)=[O:14].Cl.[NH2:23][OH:24]>>[CH:7]1[CH:12]=[C:11]2[C:13]([N:23]([OH:24])[C:16]([C:18]3=[CH:19][CH:20]=[CH:21][C:9](=[C:10]23)[CH:8]=1)=[O:15])=[O:14]
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C1c2cccc3cccc(c23)C(=O)N1O

Procedure:
To 400 g of an aqueous solution of 3% by weight sodium carbonate were added 24.0 g of 1,8-naphthalic acid anhydride and 10.0 g of hydroxylamine hydrochloride and they were reacted for 2 hours at 90° C. Then, 200 g of an aqueous solution of 10% by weight sodium carbonate was added to the mixture, after filtering away insoluble materials, 100 ml of concentrated hydrochloric acid was added to the mixture, and precipitates formed were collected and recrystallized from ethanol to provide N-hydroxy-1,8-naphthalimide.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])C.[O-]CC.[Na+]>>[C:14]([CH:13]1[C:4](=[O:5])[C:6]2[N:7]=[CH:8][S:9][C:10]=2[CH2:11][CH2:12]1)([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CCCc1scnc1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C1CCc2scnc2C1=O
Yield: 67 %

Procedure:
This compound is prepared from the product obtained in step (b), by cyclization with sodium ethoxide, according to the procedure of Example 1(c). The desired product crystallizes from isopropyl oxide. M.p.=81°-82° C. Yield: 67%.