Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:26]=3)[C:23](O)=[O:24])[CH:16]=2)[NH:11][N:10]=1.C1[CH:32]=[CH:31][C:30]([CH2:33][NH:34]S(C2C=CC3N=NN(O)C=3C=2)(=O)=O)=CC=1.Cl.CCN=C=NCCCN(C)C.Cl.N1CCCC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:26]=[C:22]([C:23]([N:34]4[CH2:33][CH2:30][CH2:31][CH2:32]4)=[O:24])[CH:21]=[N:20][CH:19]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: O=S(=O)(NCc1ccccc1)c1ccc2nnn(O)c2c1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cncc(C(=O)O)c3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cncc(C(=O)N4CCCC4)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 1 %

Procedure:
(5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-nicotinic acid (350 mg, 62% pure, 0.63 mmol) was dissolved in anhydrous DMF (20 mL) at 50-60° C. and the solution was cooled to room temperature when PS-HOBt resin (Argonaut Technologies) (0.9 mmol·g−1 loading, 2.20 g, 1.98 mmol), DMAP (32 mg, 0.26 mmol) and EDCl (375 mg, 1.95 mmol) were added. The mixture was shaken at room temperature for 16 h. The resin was filtered off, washing six times with DMF and subsequently three times with ether and dried. The resin and (5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-nicotinate) (460 mg, theoretical loading 105 μmol) were suspended in anhydrous DMF (3 mL) containing pyrrolidine (110 μl, 1.3 mmol) and shaken for 22 h. The resin is filtered off, washing with dichloromethane, ether and DMF. The filtrate and washings were combined and concentrated. The resulting residue is purified by mass-triggered reverse phase HPLC using a gradient of acetonitrile in water containing 0.1% of formic acid to afford {5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridin-3-yl}-pyrrolidin-1-yl-methanone (2.4 mg, 6 μmol, 6% yield) as a light brown solid. 1H-NMR (500 MHz, d6-MeOH) δ 8.98 (d, 1H), 8.87 (d, 1H), 8.74 (d, 1H), 8.50 (d, 1H), 8.31 (t, 1H), 7.67 (dd, 1H), 7.48 (ddd, 1H), 7.21 (d, 1H), 7.11 (dt, 1H), 3.89 (s, 3H), 3.65 (t, 2H), 3.58 (t, 2H), 2.02 (m, 2H), 1.96 (m, 2H). MS: m/z 400 [MH+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:16][C:17](=[O:29])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([C:27]#[N:28])([CH3:26])[CH3:25])[CH:19]=3)[CH:12]=[CH:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[C:30]([N:35]=[C:36]=[S:37])(=[O:34])[O:31][CH2:32][CH3:33].O>CS(C)=O>[C:27]([C:24]([C:20]1[CH:19]=[C:18]([C:17]([NH:16][C:11]2[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([CH:10]=2)[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:36]([NH:35][C:30](=[O:34])[O:31][CH2:32][CH3:33])=[S:37])=[N:7][CH:6]=2)=[O:29])[CH:23]=[CH:22][CH:21]=1)([CH3:26])[CH3:25])#[N:28]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)nc1
Reactant: CCOC(=O)N=C=S
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cc(NC(=O)c3cccc(C(C)(C)C#N)c3)ccc2C)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (4.71 g, 12.2 mmol) in dimethyl sulfoxide (100 mL) was added ethyl isothiocyanatocarbonate (1.73 mL, 14.6 mmol), and the mixture was stirred at room temperature for 6 hr. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL, 50 mL). The combined organic layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl ({5-[5-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)-2-methylphenoxy]pyridin-2-yl}carbamothioyl)carbamate as a yellow amorphous solid. The obtained compound was used in the next reaction without further purification.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:8][C:9]([C:11]1[N:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1)=[O:10])[CH:6]=[CH2:7].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C(O)(=O)C>CO>[CH2:5]([O:8][C:9]([C:11]1[N:12]([NH:16][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)[CH:13]=[CH:14][CH:15]=1)=[O:10])[CH:6]=[CH2:7]
Reactant: C=CCOC(=O)c1cccn1N
Reactant: O=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCOC(=O)c1cccn1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.4 %

Procedure:
Sodium cyanoborohydride (2.29 g, 36.4 mmol) was added to a solution of 1-amino-1H-pyrrole-2-carboxylic acid allyl ester (Example 1b, 3.03 g, 18.2 mmol), 4-fluorobenzaldehyde (1.96 mL, 18.3 mmol) and acetic acid (6 mL), in methanol (120 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo to a volume of about 30 mL. The remaining liquid was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and a 1:1 mixture of ethyl acetate and hexanes (2×200 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 0→40% ethyl acetate in hexanes) afforded the desired product, 1-(4-fluoro-benzylamino)-1H-pyrrole-2-carboxylic acid allyl ester (1.87 g, 6.8 mmol, 37% yield) as a clear liquid. 1H NMR (400 MHz, CDCl3) δ: 4.08 (2H, d, J=5.4 Hz), 4.75-4.77 (1H, m), 5.27-5.30 (1H, m), 5.37-5.41 (1H, m), 5.95-5.97 (1H, m), 5.98-6.05 (1H, m), 6.58-6.61 (1H, m), 6.75-6.76 (1H, m), 6.89-6.91 (1H, m), 6.97-7.01 (2H, m), 7.22-7.25 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][NH:10][CH2:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CCNCCc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
4-Nitrophenethylamine (4 g), 4-nitrophenethyl bromide (5.54 g) and potassium carbonate (3.32 g) were heated under reflux in acetonitrile (50 ml) for 2 days. The solvent was then evaporated, the residue taken up in ethyl acetate and washed three times with aqueous sodium carbonate and three times with brine. The organic phase was dried (Na2SO4), filtered and evaporated, and the residual oil was purified by chromatography on silica eluting with methylene chloride containing methanol (0% up to 5%). The product-containing fractions were combined and the solvent evaporated to give a solid which was recrystallised from ethyl acetate/hexane to give the title compound, yield 2.0 g, m.p. 86°-91°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[CH2:15](Br)[CH:16]=[CH2:17]>>[CH2:17]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:14])[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Product: C=CCC1Cc2cc(OC)c(OC)cc2C1=O

Procedure:
The title compound 78 is prepared according to the procedure reported in step A of Example 17 with 5,6-dimethoxy-1-indanone (1 g, 5.2 mmol) and allyl bromide (0.86 mL, 7.17 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 78 as a colorless oil. (Yield 0.5 g, 46%).
Reaction SMILES: [H-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[F:7][C:8]1[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:9]=1[C:10](O)=[O:11].Cl>CN(C)C=O>[F:7][C:8]1[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:9]=1[C:10](=[O:11])[CH2:6][N+:3]([O-:5])=[O:4]
Reactant: C[N+](=O)[O-]
Reactant: CS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(F)c(C(=O)C[N+](=O)[O-])c1
Temperature: 0 °C
Yield: 86.5 %

Procedure:
60% Sodium hydride (3.0 g) was suspended in 20 ml of N,N-dimethylformamide, then 8.4 g of nitro-methane was gradually dropped thereinto with ice-cooling and stirring and the mixture was stirred at room temperature for 30 minutes. 2-Fluoro-5-methanesulfonylaminobenzoic acid (8.0 g) and 6.7 g of N,N'-carbonyldiimidazole were dissolved in 30 ml of N,N-dimethylformamide and the solution was made to react at room temperature for 1 hour. The reaction mixture was added, with ice-cooling, to the solution obtained hereinbefore and the mixture was stirred at room temperature for 2 hours. Then, the mixture was poured into ice water, acidified with hydrochloric acid and the crystals separated out therefrom were filtered, washed with small amount of ethanol and dried to give 8.2 g of 4'-fluoro-3'-(2-nitroacetyl)-methanesulfonanilide, m.p. 174°-176 ° C.
Reaction SMILES: [OH-].[K+].O=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1([CH2:19][C:20](=[O:22])[CH3:21])C(OCC)=O>O>[CH:21]1[C:20](=[O:22])[CH2:19][CH:5]2[CH2:6][CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]=12
Reactant: CCOC(=O)C1(CC(C)=O)CCc2ccccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1C=C2c3ccccc3CCC2C1

Procedure:
500 ml of water and 40 g of KOH are charged into a 1 liter glass flask, containing 43 g of 2-ethoxycarbonyl-2-(2-oxopropyl)-α-tetralone (XV), 65% purity, obtained as described above. The mixture is then heated to reflux temperature for 10 hours, the reaction trend being followed by means of TLC.
Reaction SMILES: [CH:1]1([C:6]([NH:8][C:9]2[N:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pt]=O>[CH:1]1([C:6]([NH:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Nc1ncc([N+](=O)[O-])cn1)C1CCCC1
Agent: O=[Pt]
Solvent: CCO
Product: Nc1cnc(NC(=O)C2CCCC2)nc1
Reaction time: 1 h
Yield: 73.2 %

Procedure:
Platinum oxide (50 mg, 0.22 mmol) was added to a solution 2-(N-cyclopentanoyl)amino-5-nitropyrimidine (808 mg, 3.42 mmol) in ethanol (100 ml) at ambient temperature and the reaction stirred for 1 hour under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and the solvents were evaporated in vacuo. Trituration with diethylether and drying yielded 2-(N-cyclopentanoyl)amino-5-aminopyrimidine (516 mg, 73% yield) as brown solid:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](=[O:24])[C:8](=[N:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:9]([C:8]1[C:7](=[O:24])[C:3]2[O:4][CH:5]=[CH:6][C:2]=2[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:12]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(=O)c1occc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)c2ccoc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
A suspension of 1-(3-bromofuran-2-yl)-2-{[3-(trifluoromethyl)phenyl]hydrazono}butane-1,3-dione (1.59 g) and potassium carbonate (0.817 g) in DMF (10 mL) was stirred at 90° C. for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from hexane/ethyl acetate to give the title compound (683 mg).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=1)=[C:8]2[O:31][CH:32]([F:34])[F:33]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(C(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
A solution of [8-chloro-4-difluoromethoxy-2-ethyl-3-(4-isobutyrylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.22 g) in tetrahydrofuran (5.0 mL) and water (1.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.86 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated to low bulk under reduced pressure, and the pH adjusted to 4-5 by the addition of 1.0 M aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave title compound (0.18 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:23](COCC[Si](C)(C)C)[N:24]=[CH:25][N:26]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:26]=[CH:25][NH:24][N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ncnn4COCC[Si](C)(C)C)nn23)no1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nc[nH]n4)nn23)no1
Temperature: 60 °C
Yield: 16.1 %

Procedure:
To a solution of 3-(5-methylisoxazol-3-yl)-6-[2-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,4-triazolyl]methyloxy-1,2,4-triazolo-[3,4-a]phthalazine (1.20 g, 2.5 mmol) in ethanol (20 ml) was added 2N hydrochloric acid (40 ml) at room temperature. The mixture was heated at 60° C. for 5 h, saturated potassium carbonate solution was added and the solvent evaporated in vacuo. The solid was triturated with ethanol, filtered and the filtrate evaporated in vacuo. The residue was flash chromatographed on silica gel, eluting with 4% methanol/dichloromethane, to give the title-product (140 mg, 16%), mp 260-262° C.; 1H NMR (360 MHz, d6-DMSO) δ 2.56 (3H, s, me), 5.75 (2H, s, CH2), 7.24 (1H, s, Ar—H), 8.00 (1H, t, J=8.1 Hz, Ar—H), 8.14 (1H, t, J=7.7 Hz, Ar—H), 8.26 (1H, d, J=8.0 Hz, Ar—H), 8.60 (1H, br s, NH), 8.65 (1H, d, J=7.4 Hz, Ar—H); MS (ES30) m/e 349 NH]+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C@H:15]2[CH2:18][C@@H:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16]2)[C:13]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([O:19][C@@H:17]1[CH2:18][C@H:15]([N:14]2[C:13]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution of [(S)-1-[1-(cis-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethyl]carbamic acid tert-butyl ester (570 mg, 1.3 mmol) in DCM (10 mL) was added TFA (4 mL) and the mixture stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting residue dissolved in DCM and loaded onto SCX-2 (20 g). The cartridge was washed with DCM then MeOH and then 2M NH3 in MeOH solution. The relevant fractions were concentrated in vacuo to afford the title compound as yellow gum (320 mg, 73%). LCMS (Method J): RT 1.97 min [M+H]+ 340. 1H NMR (CDCl3, 400 MHz): δ 7.69-7.55 (2H, m), 7.44-7.24 (5H, m), 7.0 (1H, dt, J=11.8, 2.5 Hz), 4.81-4.66 (1H, m), 4.53 (2H, s), 4.32-4.21 (1H, m), 4.08-3.95 (1H, m), 3.02-2.75 (4H, m), 1.90 (2H, s, br), 1.50 (3H, d, J=7.0 Hz)-NMR: 328174
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8]O)[CH3:2].[CH2:10]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][CH:23]2[C:28]([N:30]([C:37]1[CH:38]=[N:39][C:40]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:42]=1)[CH2:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][CH:23]2[C:28]([N:30]([CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH:36]=1)[C:37]1[CH:38]=[N:39][C:40]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:42]=1)=[O:29])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCOCCOCCO
Product: CCOCCOCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment of diethylene glycol monoethyl ether (1.5 mL) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.72 g) in the same manner as in Example 394, 5-benzyloxy-N-({1-[2-(2-ethoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.89 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:11]=2[C:12](O)=[O:13])[CH2:7]1.Cl.[NH2:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:11]=2[C:12]([NH:28][C:29]2([C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)[CH2:31][CH2:30]2)=[O:13])[CH2:7]1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)c(F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4ccc(F)c(F)c4)C3)CC2)cc1
Yield: 54.7 %

Procedure:
The title compound (D179) (80 mg) was prepared according to the experimental procedure described in Description 144 starting from 2-(3-(3,4-difluorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D128) (100 mg, 0.267 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (60.83 mg, 0.267 mmol).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)=O.[N-:17]=[C:18]=[S:19].[K+]>O.Cl>[F:14][C:13]([F:16])([F:15])[O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[NH:17][C:18](=[S:19])[NH:2][CH:3]=2)=[CH:7][CH:8]=1
Reactant: [N-]=C=S
Reactant: NCC(=O)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2c[nH]c(=S)[nH]2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
490 mg (1.89 mmol, 1 eq) of 2-amino-1-(4-(trifluoromethoxy)phenyl)ethanone hydrochloride and 320 mg (8.62 mmol, 4.5 eq) of potassium isothiocyanate are dissolved in 5 ml of water in the presence of 1 ml of a 2M hydrochloric acid solution. The reaction mixture is stirred at 100° C. for 16 hours. 320 mg (8.62 mmol, 4.5 eq) of potassium isothiocyanate are added and the reaction mixture is stirred at 100° C. for 16 hours. The medium is filtered and then the solid is washed with water. 320 mg of 4-(4-(trifluoromethoxy)phenyl)-1,3-dihydroimidazole-2-thione are collected.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:9]=2[CH3:16])[S:4][C:3]=1[CH:17]1[O:21]CCO1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[O:29]C>>[F:22][C:23]1[CH:24]=[C:25]([C:2]2[C:6]([CH3:7])=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=3[CH3:16])[S:4][C:3]=2[CH:17]=[O:21])[CH:26]=[CH:27][C:28]=1[OH:29]
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)c(C)c1
Reactant: COc1ccc(B(O)O)cc1F
Product: Cc1cc(O)ccc1-c1sc(C=O)c(-c2ccc(O)c(F)c2)c1C
Yield: 44.9 %

Procedure:
Starting from 2-[3-bromo-5-(4-methoxy-2-methylphenyl)-4-methylthien-2-yl]-1,3-dioxolane (0.96 g, 2.6 mmol, made in Example 11, Step 1) and substituting 3-fluoro-4-methoxyphenylboronic acid (0.57 g, 3.4 mmol) in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.40 g, 67%) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])=[CH:11][N:10]=1)(C)(C)C.Cl>CCOC(C)=O>[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])=[CH:11][N:10]=1
Reactant: COc1cc2c(C(=O)N3CCc4ccccc4C3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(C(=O)N3CCc4ccccc4C3)cnc(CN)c2cc1OC

Procedure:
A solution of [4-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-6,7-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester (81 mg, 0.17 mmol) in 2 mL EtOAc was treated with HCl (6N in dioxane) according to Example 1 to give (1-Aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone as the hydrochloride salt (77 mg, 93%). MS: APCI (M+H) calc'd for C22H23N3O3+H 378.4; found 378.1.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:3]=12.[Cl:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[ClH:17].[CH2:21]([O:20][C:18]([N:15]1[CH2:14][CH2:13][CH2:12][C:4]2=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]([CH3:1])=[C:3]2[CH2:16]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: Cc1c2c(nc3ccccc13)CCCNC2
Product: CCOC(=O)N1CCCc2nc3ccccc3c(C)c2C1
Product: Cl
Yield: 58 %

Procedure:
2,3,4,5-Tetrahydro-11-methyl-1H-2-azepino[4,3-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]CC2C=CC=CC=2)[CH:6]=[CH:5][C:4]=1[C:17]1[NH:25][C:24]2[C:19](=[N:20][C:21]([O:26]CC3C=CC=CC=3)=[N:22][CH:23]=2)[N:18]=1.[H][H].[OH-].[Na+].O>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:17]1[NH:25][C:24]2[CH:23]=[N:22][C:21](=[O:26])[NH:20][C:19]=2[N:18]=1
Reactant: [H][H]
Reactant: COc1cc(OCc2ccccc2)ccc1-c1nc2nc(OCc3ccccc3)ncc2[nH]1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(O)ccc1-c1nc2[nH]c(=O)ncc2[nH]1

Procedure:
Three grams of 8-(2-methoxy-4-benzyloxy-phenyl)-2-benzyloxypurine are dissolved in 100 ml of ethanol and hydrogenated in the presence of 1 gm of 20% palladium/charcoal for two hours at 50° C. with hydrogen at 5 bar. The catalyst is filtered off and washed with hot ethanol. The filtrates are evaporated, and the residue is triturated with methylene chloride. The solid product obtained is stirred with 30 ml of 2N sodium hydroxide solution. The solution is filtered, and the filtrate is acidified with glacial acetic acid. The precipitate formed is separated from the solution by centrifuging and purified by triturating with acetone. The product contains 1 mol of water of crystallization.