Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:13][CH3:14])([CH3:12])[CH3:11])=[CH:6][CH:5]=1>O>[CH3:14][O:13][C:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:3]=[O:2])=[CH:9][CH:8]=1)([CH3:12])[CH3:11]
Reactant: COC(OC)c1ccc(C(C)(C)OC)cc1
Solvent: O
Product: COC(C)(C)c1ccc(C=O)cc1
Temperature: 25 °C
Yield: 20837.8 %

Procedure:
1.9 kg of 4-(1-methoxy-1-methylethyl)-benzaldehyde dimethyl acetal and 1.8 kg of water were refluxed (bottom temperature 87° C.) for about 1 hour, while stirring. Thereafter, the mixture was cooled to about 25° C., the phases were separated and the organic phase was distilled under a top pressure of 4 mbar and at 105°-108° C. (top temperatures). This gave 1,314.6 kg of 4-(1-methoxy-1-methylethyl)-benzaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].[Cl:11][C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17](Cl)[C:13]=1[C:14]([OH:16])=[O:15].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:11][C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1c(Cl)c([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: CCOc1ccc(N)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Nc2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 10.5 g of 4-ethoxyaniline in 250 ml acetonitrile was added over a 1.5 hour period to a solution of 20 g of 2,6-dichloro-3,5-dinitrobenzoic acid and 11 g of N,N-diisopropylethylamine in 400 ml of acetonitrile and stirred at room temperature for five hours. After the solvent was removed in vacuo, the residue was dissolved in 500 ml of chloroform and extracted with several portions of 5% ammonium hydroxide. The aqueous extracts were washed with chloroform and acidified with dilute acid. The resulting solid was collected by filtration and was washed with water to provide 2-chloro-6-[(4-ethoxyphenyl)amino]-3,5-dinitrobenzoic acid, mp 202°-206° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)o1
Solvent: CCN(CC)CC
Product: Clc1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
4,5-Diphenyloxazolone from Step 1 (30 g, 0.126 mol), triethylamine (12.8 g, 0.126 mol), and phosphorous oxychloride (96.6 g, 0.63 mol) were stirred at reflux for 4.0 hours. The mixture was concentrated in vacuo, dissolved in ether (250 mL), washed with 1N HCl, brine, and water, dried over MgSO4 and concentrated to a light yellow oil which was used in the next step without further purification or characterization.
Reaction SMILES: C(=O)([S:3][CH2:4][C:5]1([CH3:11])[CH2:9][O:8][C:7](=[O:10])[NH:6]1)C.[OH-].[Na+].O>CO>[SH:3][CH2:4][C:5]1([CH3:11])[CH2:9][O:8][C:7](=[O:10])[NH:6]1
Reactant: CC(=O)SCC1(C)COC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(CS)COC(=O)N1
Reaction time: 2.5 h

Procedure:
To a solution of S-(4-methyl-2-oxooxazolidin-4-yl)methyl ethanethioate (6.07 g, 31.2 mmol) in methanol (30 ml) was added 5.0 M NaOH in H2O (10 ml, 50 mmol). The solution was stirred for 2.5 hour, concentrated in vacuo, suspended in ethyl acetate (400 ml), washed three times with 100 ml 5% NaHSO4, 100 ml saturated NaCl, dried on MgSO4, and concentrated in vacuo. The material was used without any further purification. LRMS (ESI/APCI) m/z 148 [M+H]+.
Reaction SMILES: COC(=O)[C:4]1C=C[C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.NC1[S:35]C=CN=1>>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[S:13][CH2:12][C:11]([NH:10][C:7]2[S:35][CH:4]=[CH:5][N:6]=2)=[O:31])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Reactant: Nc1nccs1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2nccs2)cc1

Procedure:
The product from Example 1, Part C (350 mg, 1.1 mmol) and 2-aminothiazole (131 mg, 1.3 mmol) were converted to the title compound by the method described in Example 1, Part D (122 mg, 34%). 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=3.5 Hz, 1H); 7.22 (d, J=8.8 Hz, 2H); 7.02 (d, J=3.6 Hz, 1H); 7.22 (d, J=8.5 Hz, 2H); 5.11 (d, J=14.6 Hz, 1H); 4.61 (s, 1H); 4.17 (d, 14.6 Hz, 1H); 3.76 (s, 3H); 3.06 (s, 2H); 1.93 (s, 3H); 1.79 (s, 3H). MS: m/z (MH+) 404.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][OH:7].C(O[CH:17](OCC)[CH2:18][CH2:19][Cl:20])C.Cl>O>[Cl:20][CH2:19][CH2:18][CH:17]1[C:8]2[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6][O:7]1
Reactant: COc1cccc(CCO)c1OC
Reactant: CCOC(CCCl)OCC
Agent: Cl
Solvent: O
Product: COc1ccc2c(c1OC)CCOC2CCCl
Reaction time: 0.42 h
Yield: 85.2 %

Procedure:
To a mixture of 20 g of 2,3-dimethoxyphenethyl alcohol and 22 g of β-chloropropionaldehyde diethyl acetal was added 30 ml of concentrated hydrochloric acid, followed by heating at 60°-85° C with stirring for 25 minutes. After cooling, the reaction mixture was diluted with 100 ml of water and extracted with ethyl acetate. The extract was rinsed with water, dehydrated, treated with activated carbon and concentrated under reduced pressure. By the above procedure was obtained 24 g of 1-(2-chloroethyl)-5,6-dimethoxyisochroman as a colorless oil. Together with 15 ml of piperidine, 3 of this oil was heated under reflux for 2 hours, with constant stirring. After cooling, the reaction mixture was concentrated and the residue was diluted with 100 ml of water and extracted with ethyl acetate. The extract was rinsed with water, dried and concentrated under reduced pressure. The oily residue was chromatographed on a column of silica gel, elution being carried out with a 9:1 mixture of chloroform and methanol. By this procedure was obtained 2.7 g of 5,6-dimethoxy-1-(2-piperidinoethyl)isochroman as an oil. This oil was dissolved in 10 ml of alcoholic hydrochloric acid, followed by addition of ethyl ether. The mixture was left standing, whereby 1.5 g of 5,6-dimethoxy-1-(2-piperidinoethyl)-isochroman hydrochloride was obtained as colorless crystals, melting point: 178°-180° C.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5](=[NH:9])OCC.[OH:10][CH2:11][C:12]([CH2:14]O)=O.[NH3:16]>>[CH3:2][O:3][CH2:4][C:5]1[NH:9][CH:14]=[C:12]([CH2:11][OH:10])[N:16]=1
Reactant: CCOC(=N)COC
Reactant: O=C(CO)CO
Reactant: N
Agent: Cl
Product: COCc1nc(CO)c[nH]1

Procedure:
A 307.2 gm. portion of ethyl 2-methoxyacetimidate hydrochloride [Rule, J. Chem. Soc. 113, 9 (1918)] and 180 gm. of 1,3-dihydroxyacetone in 1 liter of liquid ammonia are reacted as described in Example 3 giving the desired product as an oil. A crystalline picrate salt (m.p. 175°-178° C.) is obtained by heating the oily product and picric acid in water.
Reaction SMILES: O1CCCCC1C1[CH:8]=[C:9]([CH:20]=[CH:21][C:22]2[CH:23]=[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([CH3:42])([CH3:41])[O:34]C3CCCCO3)[CH:25]=[CH:26][CH:27]=2)C=C(OC2CCCCO2)C=1.C(O)(=[O:45])C.[CH2:47]1[CH2:51][O:50][CH2:49][CH2:48]1>O>[OH:34][C:33]([CH3:42])([CH3:41])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:24]1[CH:23]=[C:22]([CH:21]=[CH:20][C:9]2[CH:8]=[C:51]([OH:50])[CH:47]=[C:48]([OH:45])[CH:49]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: C1CCOC1
Reactant: CC(=O)O
Reactant: CC(C)(CCCCCc1cccc(C=Cc2cc(OC3CCCCO3)cc(C3CCCCO3)c2)c1)OC1CCCCO1
Solvent: O
Product: CC(C)(O)CCCCCc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 8(k), by reacting 4.50 g (7.6 mmol) of 2-[6-(3-{2-[3-(tetrahydropyran-2-yl)-5-(tetrahydropyran-2-yloxy)phenyl]-vinyl}phenyl)-1,1-dimethylhexyloxy]tetrahydropyran with the solution of 100 ml of acetic acid, 50 ml of THF and 25 ml of water, and after purification on a silica column (ethyl acetate 50-heptane 50), beige crystals (m=1.23 g; Y=48%) are obtained. m.p.=98-100° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:23][CH3:24])[C:5]([N:8](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:6][CH:7]=1.[F:25][CH:26]([F:48])[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH2:40][C@@H:41]([OH:43])[CH3:42])[N:34]=2)[C:30]([Sn](C)(C)C)=[N:29]1>CN(C=O)C.CO.O.[Cu](I)I>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:30]2[C:31]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH2:40][C@@H:41]([OH:43])[CH3:42])[N:34]=3)=[CH:32][N:28]([CH2:27][CH:26]([F:48])[F:25])[N:29]=2)=[N:3][C:4]=1[O:23][CH3:24]
Reactant: COc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C[C@H](O)CNc1nccc(-c2cn(CC(F)F)nc2[Sn](C)(C)C)n1
Agent: I[Cu]I
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(-c2nn(CC(F)F)cc2-c2ccnc(NC[C@H](C)O)n2)cnc1N
Temperature: 10 °C
Yield: 34.6 %

Procedure:
A mixture of di-tert-butyl (5-bromo-3-methoxypyrazin-2-yl)imidodicarbonate (517 mg, 1.28 mmol), (2S)-1-({4-[1-(2,2-difluoroethyl)-3-(trimethylstannyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol (570 mg, 1.28 mmol), Copper iodide (5 mg, 0.026 mmol) in DMF (13 mL) was deoxygenated with a N2 bubbler for a few minutes before adding Tetrakis(triphenylphoshine)palladium (0) (74 mg, 0.064 mmol). The mixture was sealed in a microwave vial and heated in an oil bath at 10° C. for 18 hrs. This mixture was then heated in the microwave at 170° C. for 20 minutes to themolyze the tert-butoxycarbonyl groups. The mixture was partitioned between ethyl acetate and saturated aqueous NaCl. Some dark insoluble solids did not go into either phase and were removed by filtration. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organics were washed once each with water and saturated aqueous NaCl, dried over Magnesium sulfate and reduced to minimum volume. The residue was then purified on silica gel using a gradient of 0-8% methanol (containing 10% ammonium hydroxide) in a mixture of tert-butyl methyl ether and dichloromethane (1:1) as eluent. A small amount of the product still containing the tert-butoxycarbonyl groups was recovered from the column. This material was treated with 10% hydrochloric acid in methanol at 70° C. for 2 hours to complete the deprotection. The mixture was partitioned between aqueous Sodium bicarbonate and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with water (1×), saturated aqueous NaCl (1×), dried over MgSO4 and reduced to minimum volume. The residue was then purified on silica gel in a similar fashion to obtain a second batch of product. The batched were combined and dissolved in a mixture of methanol and water then lyophilized to give 180 mg (33%) (2S)-1-({4-[3-(5-amino-6-methoxypyrazin-2-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol (I-1) as a fluffy white solid. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.05-8.15 (m, 2H), 7.83 (s, 1H), 6.65 (d, J=5.31 Hz, 1H), 6.27 (tt, J=54.95, 3.79 Hz, 1H), 5.73 (br. t, J=4.93 Hz, 1H), 5.34 (br. s., 2H), 4.58 (td, J=14.72, 3.66 Hz, 2H), 3.81 (br. s., 1H), 3.76 (s, 3H), 3.54 (br. s., 1H), 3.27-3.41 (br. m, 1H), 3.06-3.23 (br. m, 1H), 1.08 (d, J=6.32 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].CCN(CC)CC>CCO.[Pd]>[NH2:6][CH2:5][C:4]1[CH:7]=[CH:8][N:9]=[C:2]([NH2:1])[CH:3]=1
Reactant: N#Cc1ccnc(N)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: NCc1ccnc(N)c1
Reaction time: 12 h
Yield: 88.9 %

Procedure:
In a sealed flask, a well stirred mixture of 2-amino-isonicotinonitrile (12.6 g, 106.0 mmol), Et3N (98 mL) and Pd/C 10% (15.0 g) in EtOH (400 mL) was placed under an H2 atmosphere (50 psi) and hydrogenated at RT for 12 h. The catalyst was filtered through a Celite pad and washed with MeOH. The filtrate was concentrated to dryness to yield the title compound (11.6 g, 94.2 mmol, 89%) as a white solid, which was used without further purification. MS: 122 [M−1]+; HPLC: AtRet=0.16.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:22]=[CH:21][C:11]3[NH:12][C:13]([C:15]4[CH:19]=[CH:18][N:17](N)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1.C(O)C([NH2:39])(CO)CO>C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]([C:19]2[C:15]([C:13]3[NH:12][C:11]4[CH:21]=[CH:22][C:8]([CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:9][C:10]=4[N:14]=3)=[N:16][NH:17][CH:18]=2)[C:31]([NH2:39])=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nn1ccc(-c2nc3cc(CN4CCOCC4)ccc3[nH]2)n1
Reactant: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: NC(=O)N(c1ccc(F)cc1)c1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
To 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-ylamine (Example 1E) (100 mg, 0.33 mmol), in THF (2 ml), was added 4-fluorophenyl isocyanate and the mixture was stirred for about 16 hours at room temperature. Resin-supported tris-amine (800 mg, 4 mmol/g) was added and the mixture agitated for a further 4 hours. The resin was removed by filtration, the filtrate was treated with 1N KOH (2 ml, MeOH:THF; 1:3) and the solution stirred for approximately 16 hours. The mixture was then partitioned between EtOAc and H2O. The aqueous layer was further extracted with EtOAc and then the combined organic fractions washed with brine, dried (MgSO4) and evaporated to dryness. The crude solid was dissolved in DCM and triturated with hexanes to give a solid which was collected by filtration. The solid was purified by flash column chromatography [SiO2, EtOAc-MeOH (90:10)] to give 1-(4-fluorophenyl)-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-urea (30 mg, 20%) as a yellow solid (LC/MS (acidic method): Rt 2.01 min, [M−H+]− 434).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8]O)[C:5]2[C:10]([CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][CH:12]=[C:13]([Cl:14])[C:4]=2[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/[N:44]=N/C(OCC)=O)=O.C1(=O)NC(=O)C2=CC=CC=C12>O1CCCC1>[Cl:14][C:13]1[C:4]2[N:3]=[C:2]3[NH:44][CH2:8][CH2:7][N:6]3[C:5]=2[C:10]([CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][CH:12]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CCO)c12
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[2,4-Dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]ethanol (1.41 g, 4.681 mmol) in tetrahydrofuran (18 mL) were added triphenylphosphine (1.84 g, 7.022 mmol), diethylazodicarboxylate (ca. 2.2 mol/L in toluene, 3.19 mL, 7.022 mmol) and phthalimide (1.03 g, 7.022 mmol). The reaction mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the mixture containing the title compound. To a solution of the crude material in tetrahydrofuran (12 mL) and ethanol (1 mL) was added hydrazine monohydrate (2 mL). The reaction mixture was stirred at room temperature for 7 hrs. The precipitate was removed by filtration. The filtrate was concentrated in vacuo, and the residue was recrystallized with ethyl acetate/tetrahydrofuran to give the title compound as a colorless solid (725.5 mg, 2.751 mmol, 59%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.ClC1C=C([N:16]2N=[N:19][C:18]([C:21]([OH:23])=[O:22])=[N:17]2)C=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:16]=[N:17][C:18]([C:21]([OH:23])=[O:22])=[N:19]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1nnn(-c2cccc(Cl)c2)n1
Product: O=C(O)c1nnn(-c2ccc(F)cc2)n1

Procedure:
This intermediate was prepared from 4-fluoro-phenylamine in four steps according to the preparation of 2-(3-chloro-phenyl)-2H-tetrazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:29]#[N:30])[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.CO[C:34](OC)([N:36](C)C)[CH3:35].[NH2:41]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:29]#[N:30])[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:18][C:13]=2[N:12]=[C:11]2[NH:41][NH:36][C:34]([CH3:35])=[C:10]2[N:9]=1
Reactant: NN
Reactant: N#Cc1cc2c(cc1OCCCN1CCOCC1)NC(=S)CN=C2c1ccccc1Cl
Reactant: COC(C)(OC)N(C)C
Product: CC1=C2N=C(c3ccccc3Cl)c3cc(C#N)c(OCCCN4CCOCC4)cc3N=C2NN1

Procedure:
5-(2-chlorophenyl)-7-cyano-1,2-dihydro-8-(3-(4-morpholinyl)propoxy)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVk) was prepared by reacting 0.00054 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-thione (thiolactam IIk) with 1,1-dimethoxy-N,N-dimethyl-ethanamine and then hydrazine in a manner analogous to Example 55. MH+/Z=477.
Reaction SMILES: [CH:1]1[C:5]2[C:6]([Cl:10])=[N:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[I:11]N1C(=O)CCC1=O>C(Cl)Cl>[CH:2]1[NH:3][C:4]2[N:9]=[CH:8][N:7]=[C:6]([Cl:10])[C:5]=2[C:1]=1[I:11]
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ncnc2[nH]ccc12
Solvent: ClCCl
Product: Clc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound dA.23 was synthesized according to the procedure described by Ju et al. (2006, which is incorporated herein by reference). To a suspension of 6-chloro-7-deazapurine (1.00 g, 6.51 mmol) in anhydrous CH2Cl2 (55 mL) was added N-iodosuccinimide (1.70 g, 7.56 mmol). The reaction was protected from light while stirring at room temperature for two hours. The reaction was then concentrated down in vacuo. The material was re-crystallized from hot methanol to yield 6-chloro-7-iodo-7-deazapurine dA.23 (0.94 g, 52%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:41])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38]([OH:40])=O)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.[CH:59]1([NH:62][C:63]([C@@H:65]2[CH2:69][CH2:68][CH2:67][NH:66]2)=[O:64])[CH2:61][CH2:60]1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:41])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38]([N:66]3[CH2:67][CH2:68][CH2:69][C@H:65]3[C:63](=[O:64])[NH:62][CH:59]3[CH2:60][CH2:61]3)=[O:40])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(NC1CC1)[C@@H]1CCCN1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)c3ccccc3n2)CC1
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CC3)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.2 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 30 ml of DMF, 883 mg of EDC, 848 mg of pentafluorophenol and 885 mg of NEM was added and the reaction mixture was stirred for 2 h at RT. Then, 732 mg of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride and 442 mg of NEM in 5 ml of DMF was added. After 2 h the reaction mixture was diluted with water and extracted with DCM (3×50 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step. Yield: 2.9 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Mg].[CH:14](=[O:18])[CH:15]([CH3:17])[CH3:16]>>[CH3:16][CH:15]([CH3:17])[CH:14]([C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1)[OH:18]
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CC(C)C=O
Agent: [Mg]
Product: CC(C)C(O)c1ccc(OC(F)(F)F)cc1

Procedure:
The target compound is obtained analogously to method described for Example 1a). First of all a Grignard is prepared from 23.7 g (96 mmol) 1-bromo-4-(trifluoromethoxy)-benzene and 2.35 g (97 mmol) magnesium, which is then reacted with 7.3 g (100 mmol) isobutyraldehyde. After working up and purification by column chromatography 14.8 g of a brown oil are obtained which is further reacted directly.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:20][C:19](=O)[C:11]2[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][O:14][C:10]=2[CH2:9]1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl>C(O)C>[ClH:27].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:20]/[C:19](=[N:26]\[NH:25][C:22]([NH2:24])=[NH:23])/[C:11]2[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][O:14][C:10]=2[CH2:9]1
Reactant: O=C1CC(c2ccccc2Br)Cc2occ(C(F)(F)F)c21
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: N=C(N)N/N=C1\CC(c2ccccc2Br)Cc2occ(C(F)(F)F)c21
Temperature: 90 °C
Reaction time: 4 h
Yield: 35.6 %

Procedure:
To a mixture of 6-(2-bromophenyl)-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.29 g) and aminoguanidine hydrochloride (90 mg) were ethanol (16 ml) and 6N hydrochloric acid (0.070 ml), and the mixture was stirred at 90° C. for 4 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2-bromophenyl)-4-guanidinoimino-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 53) (0.13 g).
Reaction SMILES: C1(C)C=CC(S(O[C@@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:23][NH2:24]>C(O)C>[CH3:23][NH:24][C@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:12]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C/C=C/c2cccnc2)cc1
Solvent: CCO
Product: CN[C@@H](C)C/C=C/c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
A mixture of (2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate (9.00 g, 28.35 mmol), methylamine (200 mL, 40% solution in water), and ethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing an oil. Further purification by vacuum distillation furnished 1.20 g (24.0%) of a colorless oil, by 90-100° C. at 0.5 mm Hg.