Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([CH3:28])=[CH:22][C:21]=1B(O)O>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[C:23]([CH3:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=2[Cl:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Cl)c(B(O)O)cc1C
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Product: COc1cc(Cl)c(-c2ccnc(OCc3ccccc3)c2[N+](=O)[O-])cc1C
Yield: 39 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (924 mg, 3.49 mmol) and 2-chloro-5-methyl-4-methoxyphenylboronic acid (prepared substantially as described in Speicher, A.; Kolz, J.; Sambanje, R. P. Synthesis, 2002, 17, 2503) (770 mg, 3.84 mmol) were treated substantially as described in Part A of Example 19a to give 514 mg (39%) of 2-benzyloxy-4-(2-chloro-4-methoxy-5-methyl-phenyl)-3-nitro-pyridine: 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (d, J=5.4 Hz, 1 H), 7.47–7.44 (m, 2H), 7.40–7.30 (m, 3H), 7.00 (s, 1H), 6.94 (d, J=5.4 Hz, 1 H), 6.90 (s, 1 H), 5.55 (s, 2 H), 3.84 (s, 3 H), 2.17 (s, 3 H).
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]([N:9]=[N:10][C:11](Cl)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])([CH3:8])([CH3:7])[CH3:6].O>C(O)(C)C>[C:5]([N:9]=[N:10][C:11]([N:3]=[C:2]=[S:1])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])([CH3:6])([CH3:7])[CH3:8]
Reactant: N#C[S-]
Reactant: CC(C)(C)N=NC(C)(Cl)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)N=NC(C)(N=C=S)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 26.0 grams (0.32 moles) of sodium thiocyanate in 150 ml of 75% aqueous isopropanol cooled to 5° C. in a 500 ml erlenmeyer flask was added 71.4 grams (0.32 moles) of 1-t-butylazo-1-chloro-1-phenylethane over 3 minutes holding the temperature at 5°-10° C. with an ice bath. The reaction mixture was stirred for 90 minutes at room temperature, poured into 300 ml water and the product extracted with 100 ml of pentane. The pentane extract was washed twice with 100 ml water, once with 10% NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure. The product was a light brown liquid which weighed 43.3 grams (54.6% crude yield). The infrared spectrum of the product had a very strong broad band at 1960-2175 cm-1 which is indicative of the α-isothiocyanate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.[C:27](O)(=[O:29])[CH3:28]>C(Cl)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:27](=[O:29])[CH3:28])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:24])([F:26])[F:25])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Reactant: CC(=O)O
Solvent: CC(=O)Cl
Product: CC(=O)NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(C)cc2)cc1

Procedure:
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (0.60 g, 1.57 mmol) was heated in 2 mL acetyl chloride and 2 mL acetic acid at reflux for 2 h. An additional 2 mL acetyl chloride was added and the mixture was heated to reflux for an additional 5 h. The mixture was cooled and concentrated. Recrystallization from ether/hexane furnished the product as a white solid: Anal. Calc'd for C19H16N3O3SF3: C, 53.90; H, 3.81; N, 9.92; S, 7.57. Found: C, 54.04; H, 3.80; N, 9.93; S, 7.66.
Reaction SMILES: F[C:2]1[C:3]([CH3:19])=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:5]([O:7][CH3:8])=[O:6].CN(C)C=O.[CH3:25][S-:26].[Na+]>C(OCC)(=O)C>[CH3:19][C:3]1[C:2]([S:26][CH3:25])=[C:11]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[S-]
Reactant: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(F)c1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(SC)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
2.1 g (7.34 mmol) of methyl 3-fluoro-2-methyl-4-(pentafluoroethyl)benzoate were introduced into 20 ml of N,N-dimethylformamide and then admixed with 758 mg (95% by weight; 10.3 mmol) of sodium thiomethoxide. The mixture was stirred at RT for 2 hours and then freed from the solvent. The residue was taken up in ethyl acetate and water, the aqueous phase was extracted twice with ethyl acetate, and, finally, the combined organic phases were dried and freed from the solvent. The residue was purified by chromatography, giving 1.28 g of clean product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:21]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:20])[CH:9]([Br:21])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reaction time: 20 h

Procedure:
To a solution of the product of step 3 (40.5 g, 139 mmol) in CCl4 (500 mL) and CHCl3 (2 L) was added dropwise a solution of Br2 in CCl4 (50 mL). After addition was completed, the mixture was washed with saturated NaHCO3 (500 mL) and Na2S2O8 (2×250 mL). The pale yellow solution was dried over Na2SO4 and concentrated to dryness. The residue was stirred in 50 % EtO2 /hexane for 20 h and filtered to give 49 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[NH:7]2.[H-].[Na+].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[N:7]2[CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=1
Reactant: CN1Cc2c(Br)cccc2NC1=O
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2c(Br)cccc2N(Cc2cccc(F)c2)C1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
To a solution of 5-bromo-3-methyl-3,4-dihydro-1H-quinazolin-2-one (132 mg, 0.55 mmol) in 5 ml anhydrous dimethylformamide was added sodium hydride (33 mg of a 60% suspension in mineral oil, 0.83 mmol) portionwise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 20 minutes, at which time the initial offgassing ended. 3-Fluorobenzyl bromide (0.08 ml, 0.65 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for an hour. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting residue was purified by flash chromatography to give 156 mg of 5-bromo-1-(3-fluoro-benzyl)-3-methyl-3,4-dihydro-1H-quinazolin-2-one as a yellow solid (81%). MS: 349.1 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C:7](O)=O)[N:3]=[CH:2]1.[NH2:10][C:11]1[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14](=[O:29])[N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:16]=1[NH2:17]>>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[C:16]3[N:17]=[C:7]([CH2:6][C:4]4[N:3]=[CH:2][S:1][CH:5]=4)[NH:10][C:11]=3[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14]2=[O:29])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=C(O)Cc1cscn1
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Product: CCCn1c(=O)c2[nH]c(Cc3cscn3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 4-thiazolylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine. By methods well known in the art, 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=O.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[CH:17]=[C:4]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[C:3]3[C:2](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:1]=2)=[CH:21][CH:22]=1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Product: Fc1ccc(-c2cc(-c3ccc(F)cc3)c3ccccc3n2)cc1
Temperature: 200 °C

Procedure:
A flask is loaded with (17) (21.5 g, 0.1 mol), 4-fluoroacetophenone (13.8 g, 0.1 mol), and toluene sulfonic acid monohydrate (3.8 g, 0.02 mol). The flask is heated to 200° C. and the water of condensation removed. After water evolution ceased, the mixture is cooled and the crude solid product is crushed and washed with hot ethanol The product is further recrystallized from toluene.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([O:17]C)=[N:15][CH:16]=3)[C:3]=12.CC(O)=O>Br.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([OH:17])=[N:15][CH:16]=3)[C:3]=12
Reactant: COc1ncc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccccc3)c3ncnc(N)c23)cn1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnc(O)nc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
3-(1-(4-amino-3-(2-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (Example 55, 23.3 mg, 0.047 mmol) was dissolved in HBr 33% in CH3COOH (1 ml, 0.047 mmol) and stirred at rt for 1 h. The reaction was then diluted with water (3 mL) and the resulting mixture purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (20 mg, 88%) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][S:2]([O:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][O:7][CH3:6])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COCC(C)(C)CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)(C)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methanesulfonyl chloride (330 mL) is added dropwise to a solution of 3-methoxy-2,2-dimethylpropan-1-ol (250 mg) and N,N-diisopropylethylamine (1.1 mL) in dichloromethane (3 mL) chilled in an ice bath. The mixture is stirred at room temperature for 12 hours and partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The organic phase is washed with twice with 1 N hydrochloric acid, saturated aqueous NaHCO3 solution and brine. Then the organic phase is dried (MgSO4) and concentrated to give the title compound. Yield: 407 mg; TLC: rf=0.75 (silicagel, cyclohexane/ethyl acetate 3:1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:18][OH:19]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=[N:18][OH:19])[CH2:12][CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCCCOCCCCN1CCC(=NO)CC1

Procedure:
1-(4-Butoxybutyl)-4-piperidone oxime is prepared from 1-(4-butoxybutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [NH3:1].[C:2]([O:6][C:7]([N:9]1[CH2:12][CH:11]([C:13]2[N:17]3[CH:18]=[CH:19][N:20]=[C:21](Cl)[C:16]3=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[N:14]=2)[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CC(O)C>O>[C:2]([O:6][C:7]([N:9]1[CH2:12][CH:11]([C:13]2[N:17]3[CH:18]=[CH:19][N:20]=[C:21]([NH2:1])[C:16]3=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[N:14]=2)[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC(c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(Cl)nccn23)C1
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn23)C1
Reaction time: 8 h

Procedure:
20 M of NH3 in H2O (3 mL) was added to a suspension of 3-[8-chloro-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-azetidine-1-carboxylic acid tert-butyl ester in i-PrOH (4 mL, 0.05 mol). The mixture was heated in an oil bath set at 105° C. overnight. The solvent was removed under reduced pressure and the residue was carried on to the next step without further purification. MS (ES+): m/z 467.82 (100)[MH+]. HPLC: tR=2.66 min (Open Lynx, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[NH:19]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27])[C:20]([NH2:22])=[NH:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:21]=[C:20]([NH:19][C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([OH:28])=[O:27])[N:22]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: N=C(N)Nc1cccc(C(=O)O)c1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Product: O=C1Cc2cnc(Nc3cccc(C(=O)O)c3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to method I, 8-chloro-4-((dimethylamino)methylene)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 3-guanidino-benzoic acid were converted to I-62-a (72%): MS m/z=381 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:13]=[O:14]>CN(C=O)C>[CH2:15]([NH:12][C:13]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([OH:11])=[N:7]1)=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Oc1n[nH]c2cc(Cl)ccc12
Reactant: CCCCCCN=C=O
Solvent: CN(C)C=O
Product: CCCCCCNC(=O)n1nc(O)c2ccc(Cl)cc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
100 mg (0.59 mmol) of 6-chloro-1H-indazol-3-ol were dissolved in 5 ml of DMF. Addition of 83 mg (0.65 mmol) of 1-isocyanatohexane was followed by stirring at room temperature for 1.5 h and at 50° C. for 1 h, concentration and purification by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 17 mg (7%), M+H+: 296.14, 6-chloro-3-oxo-3H-indazole-1,2-dicarboxylic acid bishexylamide and 12 mg (5%) of 6-chloro-1-hexylcarbamoyl-1H-indazol-3-yl hexylcarbamate. It was additionally possible to isolate 6-chloro-3-hydroxyindazole-1-carboxylic acid hexylamide as compound not according to the invention.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:29][CH2:28]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[CH2:33]([N:30]1[CH2:29][CH2:28][CH:27]([O:26][C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:14]([C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:12]=3[CH3:13])=[O:16])=[CH:25][C:22]=2[C:23]#[N:24])[CH2:32][CH2:31]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N#Cc1cc(N)ccc1OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(OC3CCN(Cc4ccccc4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 29.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and 5-amino-2-(1-benzylpiperidin-4-yloxy)benzonitrile (1.2 g), the title compound (0.6 g) was obtained, melting point: 194° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[OH:11][C:12]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>CN(C=O)C>[CH3:17][O:16][C:14](=[O:15])[C:13]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:12]=1[O:11][CH2:9][CH:8]=[CH2:7]
Reactant: COC(=O)c1cc(OC)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(OC)cc1C(=O)OC
Temperature: 60 °C
Yield: 82.2 %

Procedure:
K2CO3 (4.64 g, 33.6 mmol) and allyl bromide (1.56 mL, 18.5 mmol) were added to a solution of methyl 2-hydroxy-5-methoxybenzoate (2.5 mL, 16.8 mmol) in DMF (10 mL). The reaction mixture was heated to 60° C. for 1 h, and then quenched with H2O (80 mL) and extracted with EtOAc (2×80 mL). The organic layers were washed with H2O (150 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 5-10% EtOAc/hexane to give a colorless oil (3.07 g, 82%). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=3.28 Hz, 1 H) 6.98-7.03 (m, 1H) 6.90-6.94 (m, 1 H) 6.01-6.11 (m, 1 H) 5.44-5.51 (m, 1 H) 5.25-5.31 (m, 1 H) 4.57 (td, J=3.28, 1.52 Hz, 2 H) 3.91 (s, 3 H) 3.80 (s, 3 H).
Reaction SMILES: FC(F)(F)C1C=C[C:6]([C:7](O)=[O:8])=[CH:5]C=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25](C(=O)C)=[CH:24][CH:23]=2)=[N:19][CH:20]=1>>[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:27]=2[CH2:5][CH2:6][C:7]3=[O:8])=[N:19][CH:20]=1
Reactant: CC(=O)c1ccc(Oc2ccc(N)cn2)cc1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 4-(trifluoromethyl)benzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 1-{4-[(5-amino-2-pyridinyl)oxy]phenyl}-1-ethanone obtained in Reference Example 24 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][C:17]([NH:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:18][CH:19]=3)[N:14](COCC[Si](C)(C)C)[N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][C:17]([NH:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:18][CH:19]=3)[NH:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccccc3Cl)c2)c2cnc(NCCN3CCOCC3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccccc1CNc1cccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)c1
Reaction time: 3 h

Procedure:
To a stirred solution of [3-[3-(2-chloro-benzylamino)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (120 mg, 0.202 mmol) in dichloromethane (3 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred for another three hours at this temperature. The solvent was evaporated under reduced pressure and the pH of the residue was adjusted to 8 with saturated NaHCO3. The resulting mixture was extracted with EtOAc (10 mL), dried and concentrated. It was purified by prep-HPLC to give {3-[3-(2-chloro-benzylamino)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-(2-morpholin-4-yl-ethyl)-amine. (Yield 15 mg, 61%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]=[O:18].[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:6]1[N:5]=[CH:4][C:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:17]=[O:18])=[CH:2][CH:7]=1
Reactant: OB(O)c1ccccc1O
Reactant: O=Cc1c[nH]c2ccc(-c3cnccc3Br)cc12
Product: O=Cc1c[nH]c2ccc(-c3ccc(-c4ccccc4O)nc3)cc12

Procedure:
The title compound was prepared in analogous manner as described for 2. Thus, starting from 3 (0.1 g, 0.33 mmol) and 2-hydroxy benzeneboronic acid instead of 6-bromo-3-iodopyridineboronic acid following the above described procedure gave 50 mg of pure 4.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[O:15][CH2:14]2)[CH:9]1[C:24]#[N:25])C1C=CC=CC=1.[H][H]>C(O)C.[Ni]>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:17]2[C:10]3([CH2:14][O:15][C:16]=2[CH:21]=1)[CH2:11][CH2:12][CH2:13][NH:8][CH:9]3[CH2:24][NH2:25]
Reactant: COc1ccc2c(c1)OCC21CCCN(Cc2ccccc2)C1C#N
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: COc1ccc2c(c1)OCC21CCCNC1CN

Procedure:
A mixture of 1 mmol of 1′-benzyl-6-methoxyspiro[1-benzofuran-3,3′-piperidine]-2′-carbonitrile and 50 mg of Raney-Nickel (activated by washing with water till pH 7 and washing with ethanol) in 5 ml of ethanol is hydrogenated for 12 hours under 500 psi hydrogen. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li]CCCC.[CH3:31][C:32]1[C:37]([C:38]([C:40]2[N:44]([CH3:45])[N:43]=[N:42][CH:41]=2)=[O:39])=[CH:36][CH:35]=[C:34]([CH3:46])[N:33]=1>C1COCC1>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:38]([C:37]3[C:32]([CH3:31])=[N:33][C:34]([CH3:46])=[CH:35][CH:36]=3)([C:40]3[N:44]([CH3:45])[N:43]=[N:42][CH:41]=3)[OH:39])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(c2ccc3nc(Cl)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)c2cnnn2C)c(C)n1
Temperature: -45 °C
Reaction time: 0.03 h

Procedure:
6-Bromo-2,4-dichloro-3-phenylquinoline (2.00 g, 4.62 mmol, Intermediate 3: step c) was dissolved in THF (250 mL) in a dry round bottom flask under an N2 atmosphere, then cooled to −45° C. in a dry ice acetone bath. n-BuLi (1.6 M in hexanes, 3.18 mL, 5.08 mmol) was then added dropwise via syringe over approximately 2 minutes and the resulting mixture was allowed to stir at that temperature for an additional 2 minutes. (2,6-Dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (1.10 g, 5.08 mmol, Intermediate 19: step b) in THF (15 mL) was then added to the reaction vessel via cannula over approximately 5 minutes. The reaction solution was stirred at −78° C. for approximately 5 minutes, then the dry ice bath was removed and replaced with an ice water bath and stirred at 0° C. for approximately 1 hour. The reaction was then quenched with a saturated, aqueous NH4Cl solution, then transferred to a separatory funnel with EtOAc. The organic phase was separated, then the aqueous layer was back extracted with EtOAc and the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH3 MeOH in DCM)) then further purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. For C30H25Cl2N7O, 570.5. m/z found, 570.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.27-8.22 (m, 1H), 8.07-8.02 (m, 1H), 7.84-7.77 (m, 1H), 7.73-7.67 (m, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.18-7.13 (m, 2H), 7.04-6.98 (m, 3H), 6.86 (d, J=8.2 Hz, 1H), 6.76 (d, J=8.1 Hz, 1H), 5.91 (d, J=1.9 Hz, 1H), 4.51 (s, 2H), 3.94 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H).