Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC(=O)Cc2cccc([N+](=O)[O-])c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)Cc2cccc(N)c2)c1
Yield: 93.5 %

Procedure:
To a solution of tert-butyl (3-{[(3-nitrophenyl)acetyl]amino}phenyl)carbamate (0.35 g, 0.94 mmol) in methanol (100 mL) was added 10% palladium on carbon (1:10, Palladium:carbon black, 0.15 g, 0.13 mmol). The reaction was shaken under 60 psi hydrogen gas overnight. The crude mixture was filtered through celite and concentrated under vacuum to give the desired product (0.30 g, 94%). LCMS for C19H23N3O3 (M-tBu+H)+: m/z=286.0.
Reaction SMILES: Cl[C:2]([F:26])([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH2:19][CH3:20])[C:4]=1[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C>C(O)C.[Pd]>[F:26][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH2:19][CH3:20])[C:4]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1OCC
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1OCC
Reaction time: 18 h
Yield: 47.8 %

Procedure:
A mixture of 5.0 g (0.012 mol) of product of Example 19, 1.72 ml (0.012 mol) of triethylamine and 0.75 g of 10% Pd-C in 65 ml of ethanol was hydrogenated at 40° C. under 522 kPa of Hz2 pressure for 18 hours. The reaction mixture was filtered through celite and concentrated. The residue was taken up in ether, washed with 10% HCl (aq), dried (MgSO4) and concentrated in vacuo to 3.28 g of yellow solid, which was recrystallized in hot hexane to give 2.13 g (47.4%) of product as a light yellow solid, mp 59°-61° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:6]([OH:16])[C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)[CH2:3][CH2:2]1.[H-].[Na+].F[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1>CN(C=O)C>[CH:1]1([C:4]2[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:6]([O:16][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=3)[C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(C3CC3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C3CC3)cc2c1
Yield: 86 %

Procedure:
3-Cyclopropyl-6-(methyloxy)-2-phenyl-1-naphthalenol (152) (0.18 g, 0.62 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.21 g (86%) of the title compound (153) as a yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.75-0.85 (m, 4H), 1.60-1.70 (m, 1H), 3.92 (s, 3H), 6.70 (d, J=8.6 Hz, 2H), 7.03 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 7.18-7.28 (m, 6H), 7.62 (d, J=8.7 Hz, 2H), 7.66 (d, J=9.1 Hz, 1H), 9.79 (s, 1H). LCMS (ESI): m/z 395 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.C[O-].[Na+]>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: ClCC1CO1
Reactant: OCc1cc(O)c2cc[nH]c2c1
Agent: C[O-]
Agent: [Na+]
Product: OCc1cc(OCC2CO2)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.3 g. of the 4-hydroxy-6-hydroxymethyl-indole thus prepared were dissolved in 30 ml. epichlorohydrin. To this solution were added dropwise, while stirring at ambient temperature, over the course of 1 hour, 20 ml. 2N sodium methylate solution. After about 5 hours, the starting material had reacted. The solution was evaporated in a vacuum and the residue was mixed with water, as well as with a mixture of diethyl ether and ethyl acetate. The organic phase was shaken out several times with water, subsequently dried, treated with active charcoal and evaporated. The crude 4-(2,3-epoxypropoxy)-6-hydroxymethyl-indole thus obtained (about 5 g. of a brownish oil) contains, as by-product, some 4-(2-hydroxy-3-chloropropoxy)-6-hydroxymethyl-indole but was further used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:41]([NH2:44])([CH3:43])[CH3:42])[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=1>>[CH3:40][O:39][C:37]1[CH:36]=[C:35]([C:41]([NH:44][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])([CH3:42])[CH3:43])[CH:34]=[C:33]([O:32][CH3:31])[CH:38]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: COc1cc(OC)cc(C(C)(C)N)c1
Product: COc1cc(OC)cc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)c1
Yield: 83 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-(3,5-dimethoxyphenyl)-1-methylethylamine (prepared as described in preparation 10d) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 83%.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:14]=[CH:13][C:10]([NH:11][CH3:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH3:12][NH:11][C:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:14][CH:13]=1
Reactant: CNc1ccc(C2=CCOCC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNc1ccc(C2CCOCC2)cc1
Reaction time: 8 h

Procedure:
To a solution of compound 4-(3,6-dihydro-2H-pyran-4-yl)-N-methylaniline (200 mg, 1.05 mmol) in EtOAc (20 mL) under N2 was added 10% Pd/C (50 mg) at r.t. The reaction was stirred overnight under 1 atm H2. The reaction was filtered through Celite and concentrated to give 180 mg (89%) as a yellow solid. [M+H] Calc'd for C12H15NO, 190. Found, 190.
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([N:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](=[O:17])[CH2:15][CH3:16])([CH2:10][O:11][CH3:12])[CH2:6][CH2:5]1.O(CC)CC.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>C(N(CC)CC)C>[CH3:12][O:11][CH2:10][C:7]1([N:13]([C:14](=[O:17])[CH2:15][CH3:16])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([O:1][C:35](=[O:38])[CH2:36][CH3:37])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:5][CH2:6]1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCN(CC(O)c2ccccc2)CC1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(=O)OC(CN1CCC(COC)(N(C(=O)CC)c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.8 %

Procedure:
To a stirred solution of 8.4 parts of N-[1-(2-hydroxy-2-phenylethyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide in 52.5 parts of 1,1'-oxybisethane are added 2.15 parts of propanoyl chloride and 3.8 parts of N,N-diethylethanamine. The whole is stirred for 5 hours at reflux. The reaction mixture is cooled to room temperature, poured onto water and the layers are separated. The organic phase is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 7% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is converted into the ethanedioate salt in 2-propanol. The solvent is evaporated. The oily residue solidifies on triturating in boiling 4-methyl-2-pentanone. The salt is filtered off and crystallized from 2-propanol. The product is filtered off and dried, yielding 4.6 parts (36.8%) of [2-{4-(methoxymethyl)-4-[(1-oxopropyl)phenylamino]-1-piperidinyl}-1-phenylethyl]propanoate sesquiethanedioate; mp. 171.2° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[ClH:34].O1CCOCC1>O1CCOCC1>[ClH:34].[Br:32][C:29]1[CH:30]=[CH:31][C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:33])=[O:5])[S:12][CH:13]=2)=[N:27][CH:28]=1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ccc(Br)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-[(4-{2-[(5-Bromopyridin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.72 g) synthesized in Example 293-1 was dissolved in dioxane (5 mL), 4 mol/L hydrochloric acid-dioxane (25 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, azeotroped with diethyl ether, and the precipitated solid was collected by filtration to give the title compound (1.0 g) as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23]/[C:24](=[N:31]\[O:32][CH3:33])/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6]C)=[O:5].C1COCC1.C(O)C.[OH-].[Na+]>O>[OH:1][CH:2]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23]/[C:24](=[N:31]\[O:32][CH3:33])/[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CO/N=C(\COc1ccc(COc2ccc(C(O)CC(=O)OC)cc2)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CO/N=C(\COc1ccc(COc2ccc(C(O)CC(=O)O)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a stirring solution of methyl 3-hydroxy-3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}propanoate (0.015 g, 0.0334 mmol) in the mixture of THF and Ethanol was added NaOH (0.003 g, 0.075 mmol) in 0.5 mL of water at 0° C., then stirred at RT for 2 h. After the completion of the SM reaction mass was concentrated under vacuum to remove solvents and diluted with water. Aqueous portion was neutralized with 1N HCl up to neutral pH, then extracted with ethyl acetate organic layer was washed with water and brine, dried over anhydrous Na2SO4. Evaporation under vacuum yields the titled compound as white solid (0.008 g, yield: 13.70%). Purity: 96.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:23]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24]1>ClCCl>[C:27]([CH2:26][CH2:25][CH2:24][C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1)=[O:30])([OH:29])=[O:28]
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Reactant: O=C1CCCC(=O)O1
Solvent: ClCCl
Product: CC1=NN=C(c2ccc(NC(=O)CCCC(=O)O)cc2)c2cc3c(cc2C1)OCO3
Yield: 86.6 %

Procedure:
A solution of 0.50. g (1.7 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 30 ml of anhydrous dichloromethane was stirred with 0.18 g (1.87 mmol) of glutaric acid anhydride at 20°-25° C. for 6 hours. Next day the crystals formed were filtered at 0°-5° C., washed with 3×2 ml of dichloromethane and dried at 60°-80° C. to give 0.60 g (87.0%) of the pure aimed product, m.p. 225°-227° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].C([O:13][CH:14]=[C:15]([C:21]#[N:22])[C:16](OCC)=O)C.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:14](=[O:13])[C:15]([C:21]#[N:22])=[CH:16][NH:5]2)=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: COc1ccc(N)cc1F
Solvent: CCOC(C)=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2c(=O)c(C#N)c[nH]c2cc1F
Temperature: 105 °C
Yield: 2.6 %

Procedure:
A mixture of 3-fluoro-4-methoxyaniline (15.31 g, 108 mmol) and ethyl (ethoxymethylene)cyanoacetate (18.36 g, 108 mmol) in toluene is heated at 100-110° C. for 4.5 hours then cooled to room temperature. A 1:1 mixture of hexane and ethyl acetate is added and the mixture is cooled on an ice bath. The solids are collected washing with hexane to provide a first crop of 26.10 g and a second crop of 1.24 g. A 2.0 g portion of this material is added to 18 mL of a 3:1 mixture of diphenyl ether:biphenyl that is heated to reflux. This mixture is heated at reflux for 4 hours then cooled and poured into hexane. The solids are collected by filtration and washed with ethyl acetate and hexane to provide 624 mg of 7-fluoro-6-methoxy-4-oxo-1,4,-dihydro-3-quinolinecarbonitrile as a brown solid. The filtrate is concentrated, the residue is dissolved in ethyl acetate and hexane is added. The resultant solid is collected by filtration to give 1.07 g of 7-fluoro-6-methoxy-4-oxo-1,4-dihydro-3-quinolinecarbonitrile as a yellow solid.
Reaction SMILES: [OH-].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][P:10]([OH:19])([O:12][CH:13]([N+:15]([CH3:18])([CH3:17])[CH3:16])[CH3:14])=[O:11].C(N(CC)CC)C.C1C(=O)N(O[C:35]([CH2:37][CH2:38][S:39][S:40][C:41]2[N:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:36])C(=O)C1>CS(C)=O>[OH-:9].[N:46]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:40][S:39][CH2:38][CH2:37][C:35]([C:13]([O:12][P:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH2:2])([OH:19])=[O:11])([N+:15]([CH3:17])([CH3:18])[CH3:16])[CH3:14])=[O:36]
Reactant: CC(OP(=O)(O)OCCCCCCN)[N+](C)(C)C
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(OP(=O)(O)OCCCCCCN)(C(=O)CCSSc1ccccn1)[N+](C)(C)C
Temperature: 25 °C

Procedure:
2-[(6-Aminohexoxyhydroxyphosphinyl)oxy-N,N,N-trimethylethanaminium hydroxide, inner salt (90 mg, 0.28 mmol) was dissolved in dry dimethyl sulphoxide (2 ml). Triethylamine (197 μl, 1.41 mmol) was added, followed by N-succinimidyl 3-(2-pyridyldithio)propionate (88 mg, 0.28 mmol). The mixture was stirred at ambient temperature for eighteen hours. The solvent was evaporated under vacuum at a temperature of 60° C. and re-evaporated from methanol. The residue was chromatographed on silica gel eluting with methanol. The relevant fractions were combined and evaporated to dryness to give 2[N(3-(2 pyridyldithio)propionyl)(6-aminohexoxyhydroxy
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][C:14](I)=[N:15][C:16]=3[C:7]=2[N:6]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[N:5]=1)(=[O:3])[NH2:2].[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1B(O)O.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:1]([C:4]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][C:14]([C:34]4[C:33]([F:32])=[CH:38][CH:37]=[CH:36][C:35]=4[F:39])=[N:15][C:16]=3[C:7]=2[N:6]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[N:5]=1)(=[O:3])[NH2:2]
Reactant: OB(O)c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2nc(C(N)=O)c3c2-c2nc(I)ncc2CC3)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cn2nc(C(N)=O)c3c2-c2nc(-c4c(F)cccc4F)ncc2CC3)CC1
Yield: 105.9 %

Procedure:
To a solution of tert-butyl 4-[(3-carbamoyl-8-iodo-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-1-yl)methyl]piperidine-1-carboxylate (30 mg, 0.036 mmol) in 3 ml of 1,4-dioxane and 1 ml of water, under argon atmosphere, 17.6 mg (0.11 mmol) of 2,6-difluorophenylboronic acid 13.7 mg (0.017 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium complex with dichloromethane and 54 mg (0.167 mmol) of cesium carbonate, were successively added. The mixture was submitted to microwave irradiation at 80° for 1 hour in a sealed vial. The reaction was filtered through a celite pad and the solvent evaporated to dryness. The crude was then portioned between ethyl acetate and water, the organic layer dried over sodium sulphate and the solvent removed in vacuo. After purification by flash chromatography on silica gel column (DCM/EtOAc 7/3), 20 mg (70%) of tert-butyl 4-{[3-carbamoyl-8-(2,6-difluorophenyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-1-yl]methyl}piperidine-1-carboxylate were obtained. The product was dissolved in DCM (2 ml) and 4M HCl in 1,4-dioxane (2 ml) was added. The reaction was stirred at room temperature for 1 hour, the solvent was evaporated to dryness. The solid was treated with ethyl ether and the precipitate collected by filtration to give the title compound as a pale yellow solid 17 mg (85%). LC/MS (254 nm) HPLC method 2 Rt 4.14 min. 1H NMR (401 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.57 (d, J=9.76 Hz, 1H), 8.30 (d, J=10.01 Hz, 1H), 7.55-7.69 (m, 1H), 7.45 (s, 1H), 7.37 (s, 1H), 7.23-7.33 (m, 2H), 4.57-4.66 (m, 2H), 3.16-3.26 (m, 2H), 3.01-3.14 (m, 4H), 2.69-2.85 (m, J=10.74 Hz, 2H), 2.09-2.29 (m, J=7.20 Hz, 1H), 1.56-1.70 (m, J=12.94 Hz, 2H), 1.32-1.48 (m, 2H) HRMS (ESI) calcd for C21H27IN6O3 [M+H]+ 425.1896 found 425.1896
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH2:16][CH2:15][N:14]=[C:13]1S(O)(=O)=O>CC#N>[C:1]1([N:11]=[C:13]2[NH:14][CH2:15][CH2:16][NH:12]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: O=S(=O)(O)C1=NCCN1
Solvent: CC#N
Product: c1cc2c(c(N=C3NCCN3)c1)CCCC2
Temperature: 155 °C
Yield: 13.7 %

Procedure:
5,6,7,8-Tetrahydro-1-naphthylamine (Aldrich, 159 mg, 1.06 mmol), imidazoline-2-sulfonic acid (147.0 mg, 1.0 mmol, Compound 7 obtained as described above) and CH3CN (5ml) were placed in a thick-walled cap which was sealed with a TEFLON™ screw and heated to 155° C. for 1.25 hours The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in CHCl3 and washed with aq. 1N NaOH (to pH 13). The organic layer was separated, washed with brine, dried over Na2CO3 and concentrated in vacuo to yield a brown oil The crude material was purified by flash chromatography (SiO2 ; 80:20 CHCl3 /CH3OH saturated with NH3) to yield 29.5 mg (14%) of the title compound as a white solid: mp 138°-141° C.; 1H NMR (300 MHz, CDCl3 ) & 7.05 (t, 1H) 6.82 (m, 2 H); 5.41 (br, 2H); 3.50 (s, 4H); 2.79 (m, 2H); 2.62 (m, 2H); 1.80 (m, 4H); Mass spectrum m/e 214.1339 (C13H16N3 requires 214.1344). Alternatively and preferably alcohols, most preferably isobutanol, are used instead of CH3CN in this reaction
Reaction SMILES: C(OC(=O)C)(=O)C.[NH2:8][C:9]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].C([O-])(=O)C.[K+].[N+:26]([O-])(OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:20][C:16]1[CH:17]=[C:18]2[C:9](=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=1)[NH:8][N:26]=[CH:19]2
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Reactant: CC(C)CCO[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)cc2cn[nH]c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
Acetic anhydride (4.5 g, 4.1 mL, 44 mmol) was added dropwise to the homogenous solution of methyl 2-amino-5-bromo-3-methylbenzoate (4.72 g, 19 mmol) in chloroform (55 mL) over a period of 20 min at room temperature and allowed to stir for 1 h. Potassium acetate (5.7 g, 58 mmol) and isoamyl nitrate (6.6 g, 7.6 mL, 57 mmol) were added at once to the reaction mixture under nitrogen. The clear reaction mixture turned to dark upon heating at 90° C. The reaction mixture was cooled to room temperature after overnight reflux, concentrated, diluted with water and stirred. The beige solid formed was collected by filtration and dried to obtain methyl 5-bromo-1H-indazole-7-carboxylate (2.1 g, 42%). 1H NMR (DMSO-d6): δ 13.44 (s, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 3.95 (s, 3H).LCMS: rt 6.86 min (A), purity 99%, MS (m/e) 255 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.C[O:13][C:14](=[O:43])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=3Br)[CH:25]=2)=[CH:19][C:18]=1[CH3:42]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:32]1[CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:31]=1[O:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][C:14]([OH:43])=[O:13])=[C:18]([CH3:42])[CH:19]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1cc(C(F)(F)F)ccc1Oc1cccc(Oc2ccc(CCC(=O)O)c(C)c2)c1

Procedure:
The title compound is prepared according to Example 89 by using 2-methoxyphenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 102 mg (64%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H25O5F3 522, found 523 (M+1, 100%).
Reaction SMILES: [OH:1][C:2]1([C:31](OC)=[O:32])[CH2:7][CH2:6][CH:5]([N:8]2[C:16]([NH:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[F:26])=[N:15][C:14]3[C:9]2=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=3)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:32][CH2:31][C:2]1([OH:1])[CH2:3][CH2:4][CH:5]([N:8]2[C:16]([NH:17][C:18]3[C:19]([F:26])=[CH:20][C:21]([F:25])=[CH:22][C:23]=3[F:24])=[N:15][C:14]3[C:9]2=[N:10][C:11]([NH:27][CH:28]([CH3:29])[CH3:30])=[N:12][CH:13]=3)[CH2:6][CH2:7]1
Reactant: COC(=O)C1(O)CCC(n2c(Nc3c(F)cc(F)cc3F)nc3cnc(NC(C)C)nc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(CO)CC3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Methyl 1-hydroxy-4-{2-[(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]purin-9-yl}cyclohexanecarboxylate (0.300 g, 0.6 mmol) was dissolved in 3 mL of dry methanol. The solution was cooled to 0° C. before addition of solid sodium borohydride (0.300 g, 7.92 mmol). After 1 h at low temperature, the reaction was warmed to rt and stirred overnight. The reaction was quenched with 5 mL of a saturated solution of ammonium chloride. The crude product was extracted with dichloromethane (four times). The product was purified by column chromatography (75% ethyl acetate in hexanes) followed by semi-preparative HPLC. The fractions were neutralized using a resin-exchange column. (0.101 g, 37% yield). M+1: 451.