Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[CH:14][N:13]([CH:29]3[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][OH:37])[CH2:31][CH2:30]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:37][CH2:36][CH2:35][CH:32]1[CH2:31][CH2:30][CH:29]([N:13]2[C:9]3[N:10]=[CH:11][N:12]=[C:7]([NH2:6])[C:8]=3[C:15]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:20][CH:21]=3)=[CH:14]2)[CH2:34][CH2:33]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(CCO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
Methanesulfonyl chloride (0.036 g, 0.31 mmol) was added into a solution of 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-1-ethanol (0.11 g, 0.26 mmol) and triethylamine (2.5 mL) in dichloromethane (2.5 mL) at 0° C. The mixture was allowed to warm up to ambient temperature and stirred overnight. Methanesulfonyl chloride (0.036 g, 0.31 mmol) and dichloromethane (2.5 mL) was added. The mixture was stirred at ambient temperature for 17 hours. Methanesulfonyl chloride (0.036 g, 0.31 mmol) and dichloromethane (2.5 mL) was added. The mixture was stirred at ambient temperature for 4 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using methanol/dichloromethane (5:95) as a mobile phase to yield 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}ethyl methanesulfonate (0.10 g, 0.21 mmol) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.31(s, 1H), 7.44 (d, 2H), 7.38(t, 2H), 7.15(t, 1H), 7.08 (m, 5H), 5.31(br, 2H), 4.73(m, 1H), 4.32(t, 2H), 3.03(s, 3H), 1.99-1.61(m, 11H); TLC (methanol/dichloromethane=5:95) Rf 0.37; RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6mm; 25%-100% over 10 min then 100%-25% over 2 min acetonitrile-0.05M ammonium acetate, 1 mL/min) Rt 11.45 min; MS: MH+ 507.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:11]=2)[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]1.[CH2:22]([N:24](CC)CC)C.N#CBr>O1CCCC1>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:7]([N:6]3[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]/[C:2]/3=[N:1]\[C:22]#[N:24])[S:8][CH:9]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CC1(C)COC(=N)N1c1nc(-c2ccc(C#N)cc2)cs1
Reactant: CCN(CC)CC
Agent: N#CBr
Solvent: C1CCOC1
Product: CC1(C)CO/C(=N\C#N)N1c1nc(-c2ccc(C#N)cc2)cs1
Reaction time: 8 h
Yield: 7.5 %

Procedure:
4-[2-(2-Imino-4,4-dimethyl-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl]benzonitrile (0.250 g, 0.83 mmol), prepared in Example 63, was dissolved in tetrahydrofuran (2 mL) followed by triethylamine (0.139 mL, 1 mmol) and cyanogen bromide (0.21 g, 2 mmol). The mixture was stirred overnight, filtered and the tetrahydrofuran was removed in vacuo. Purification by normal phase HPLC on a phenomenex cyano column eluting with hexane/1,2-dimethoxyethane (9:1 to 1:9) gave the title compound (0.020 g, 7%). HRMS: calcd for C16H13N5OS+H+, 324.09136; found (ESI, [M+H]+), 324.0919; HPLC purity 100% at 210-370 nm, 9.3 min; 100% at 246 nm, 9.3 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: N#N.[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH:16]=[O:17])=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].[BH4-].[Na+].O>CO>[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][OH:17])=[CH:14][N:15]=1)[CH3:10])([CH3:4])([CH3:6])[CH3:5]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(C=O)o1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(CO)o1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazole-5-carbaldehyde (457 mg, 1.79 mmol) was dissolved in MeOH (8.0 mL). NaBH4 (92 mg, 2.33 mmol) was added portionwise at 0° C. and the reaction mixture stirred at rt for 20 min. Water (16 mL) was added and the mixture extracted with EA (3×20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a colorless oil. LC-MS-conditions 02: tR=0.97 min, [M+H]+=258.32.
Reaction SMILES: CCN(CC)CC.[CH:8](=[C:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])[CH2:9][CH2:10][CH2:11][CH3:12]>CO>[CH2:8]([CH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC=C1CCCC1=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCCC1CCCC1=O
Temperature: 50 °C
Reaction time: 110 h
Yield: 93.2 %

Procedure:
In a 100 ml-volume three-way-cocked eggplant type flask whose atmosphere had been displaced with nitrogen was charged 230 mg (0.14 mmole) of Ru2Cl4 ((+)-BINAP)2 (NEt3), and 5 g (32 mmole) of 2-pentylidenecyclopentanone and 50 ml of methanol were added thereto to form a solution. The solution was put in a 100 ml autoclave having been displaced with nitrogen and stirred at 50° C. under a hydrogen pressure of 90 kg/cm2 for 110 hours to conduct a hydrogenation reaction. The solvent was removed from the reaction mixture by distillation, and the residue was purified by silica gel column chromatography using a mixed solvent of diethyl ether and hexane (1:4 by volume) as an eluent to obtain 4.6 g (percent yield: 92%) of 2-pentylcyclopentanone.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[OH:3].[OH-].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[C:1]([O:11][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:10])[C@H:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[OH:3]
Reactant: O=C(O)[C@@H](O)C1CCCCC1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)[C@@H](O)C1CCCCC1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
A solution of 500 mg (3.2 mmol) of (S)-hexahydromandelic acid and 238 mg (0.6 mmol) of tetrabutylammonium iodide in 6.5 mL of CHCl3 was treated with 6.5 mL of 0.5 N KOH and 0.38 mL (3.2 mmol)of benzyl bromide then stirred at 70° C. for 1.5 h. The reaction was cooled to rt and the layers were separated. The aqueous phase was extracted with 2×50 mL CH2Cl2. The organic phases were combined, dried over Na2SO4 and concentrated. Flash chromatography using 17:3 v/v hexanes/EtOAc as the eluant afforded 616 mg (77%) of the title compound: RF: 0.37 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.11-1.38 (m, 11H), 2.65 (d, J=6.3 Hz, 1H), 4.06 (dd, J=6.3, 3.5 Hz, 1H), 5.22 (s, 2H), 7.30-7.39 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)=[O:5])[CH3:2].[H-].[Na+].[CH3:17][Si:18]([CH3:26])([CH3:25])[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:21]([CH2:20][CH2:19][Si:18]([CH3:26])([CH3:25])[CH3:17])(=[O:23])=[O:22])[CH:10]=[CH:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2[nH]ccc2c1
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A solution of 1H-indole-5-carboxylic acid ethyl ester (10.31 g, 58.8 mmol) in dimethylformamide (50 mL) was added dropwise at 0° C. to a mixture of sodium hydride (1.83 g, 76.4 mmol) in dimethylformamide (150 mL). The resulting mixture was stirred at 0° C. for 30 min, then a solution of 2-trimethylsilanyl-ethanesulfonyl chloride (17.7 g, 88.2 mmol) in dimethylformamide (100 mL) was added slowly at 0° C. to the above mixture. After 2 h, sat. aqueous ammonium chloride (200 mL) was added, and the mixture was extracted with ethyl acetate (300 mL). After separation, the aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with brine (3×150 mL), and dried over anhydrous sodium sulfate. Solvents were removed in vacuo and the residue was subjected to flash chromatography on silica gel using 1:1.5 methylene chloride/hexanes as eluent to afford the title compound as a white solid (15.8 g, 79%). 1H-NMR (CDCl3, 500 MHz) δ 8.36 (d, J=1.5 Hz, 1H), 8.03 (dd, J 9.0, 2.0 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.50 (d, J=3.5 Hz, 1H), 6.75 (d, J=3.5 Hz, 1H), 3.94 (s, 3H), 3.21-3.18 (m, 2H), 0.84-0.80 (m, 2H), −0.06 (s, 9H). 13C-NMR (CDCl3, 125 MHz) δ 167.3, 137.7, 130.3, 128.3, 125.9, 125.5, 124.0, 112.8, 108.3, 52.2, 51.2, 10.1, −2.1. Mass spec. 354.12 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[C:14](OCC)(=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].[O-]CC.[Na+]>C(O)C>[CH:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[O:1][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:11]2=[O:13])([CH3:10])[CH3:9]
Reactant: CC(=O)c1cccc(C(C)C)c1O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2cccc(C(C)C)c2o1
Temperature: 25 °C

Procedure:
To a solution of Example 13A (2.048 g, 11.5 mmol) in ethanol (60 mL)was added diethyl oxalate (3.43 mL, 25.3 mmol) and sodium ethoxide (21% in EtOH, 12.9 mL, 34.5 mmol) and the mixture was refluxed for 30 minutes. The mixture was cooled to ambient temperature, partitioned between diethyl ether (150 mL) and water (150 mL). Hydrochloric acid (12N, 3 mL) was added and the separated organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 8-isopropyl-4-oxo-4H-chromene-2-carboxylate. After dissolving the intermediate in acetic acid (45 mL) and 12N hydrochloric acid (7.5 mL), the mixture was heated to reflux for 5.5 hours then cooled to ambient temperature. Water (400 mL) was added and the mixture was extracted with ethyl acetate (400 mL). The combined organic layers were washed with water (400 mL) and brine, dried over anhydrous sodium sulfate and filtered. The solution was concentrated under reduced pressure and vacuum dried overnight to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (d, 6H), 3.56 (m, 1H), 6.91 (s, 1H), 7.48 (t, 1H), 7.78 (dd, 1H), 7.89 (dd, 1H). MS (ESI) m/z 232.94 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[N:16]([CH2:17][C:18]([O:20]CC)=[O:19])[C:15](=[O:23])[N:14]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:13]3[CH2:34][CH2:35][C:36](=[O:37])[C:12]2=3)=[C:7]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:6]=1)#[N:4].CO.Cl>O1CCCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:15](=[O:23])[N:14]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)[C:13]3[CH2:34][CH2:35][C:36](=[O:37])[C:12]2=3)=[C:7]([S:38]([CH3:41])(=[O:39])=[O:40])[CH:6]=1)#[N:4]
Reactant: CCOC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC(=O)O
Temperature: 25 °C

Procedure:
Aqueous sodium hydroxide solution (1.0 M, 10.0 mL, 10.0 mmol) is added to a solution of ethyl 2-(4-(4-cyano-2-(methylsulfonyl)phenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)acetate (intermediate 29, 1.80 g, 3.20 mmol) in tetrahydrofuran (40 mL), and the mixture is stirred at room temperature over night. Another portion of aqueous sodium hydroxide solution (4.0 M, 2.0 mL, 8.0 mmol) and methanol (5.0 mL) is added, and mixture is stirred over night. Aqueous hydrogen chloride (1.0 M, 10 mL) is added, and the mixture is extracted with ethyl acetate. The organic layer is concentrated under reduced pressure, and the residue is purified reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 229 mg; ESI mass spectrum: [M+H]+=534; Retention time HPLC: 0.96 min (Z018_S04).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:15]2[CH2:20][NH:19][C:17](=[O:18])[CH2:16]2)=[CH:7][C:8]=1[O:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.CO[C:23]1C=CC([C@H]2CNC(=O)C2)=C[C:24]=1OC1CCCC1.C(OC)(=O)CC([O-])=O>>[CH2:10]([O:9][C:8]1[CH:7]=[C:6]([CH:15]2[CH2:20][NH:19][C:17](=[O:18])[CH2:16]2)[CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:14]1[CH:13]=[CH:12][CH:11]=[CH:24][CH:23]=1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC1CCCC1
Reactant: COc1ccc([C@H]2CNC(=O)C2)cc1OC1CCCC1
Agent: COC(=O)CC(=O)[O-]
Product: COc1ccc(C2CNC(=O)C2)cc1OCc1ccccc1

Procedure:
The compounds of the present invention may be prepared conventionally. Some of the known processes that can be used are described below. All starting materials are known or can be conventionally prepared from known starting materials. Preparation of Starting Material (Scheme I) Enantiomerically pure rolipram, 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone, and the starting material 4-(3-benzyloxy-4-methoxyphenyl)-2-pyrrolidone were prepared as shown in scheme I and in a similar fashion as described previously (J. Demnitz, et. al., Enantiodivergent synthesis of (R)-and (S)-Rolipram, Molecules, 1998, 3, 107-119). Thus, appropriately substituted benzaldehydes were condensed with monomethyl malonate to provide the corresponding methyl cinnamyl esters after decarboxylation. Conjugate addition of nitromethane using tetramethyl guanidine as base provided methyl 4-nitro-3-(substituted-phenyl)butyrate. Racemic 4-(3-benzyloxy-4-methoxyphenyl)-2-pyrrolidone was produced in 85% yield by selective reduction of the nitro group to the corresponding amine using NiCl2 and NaBH4 (Osby, J. O.; Ganem, B., Rapid and efficient reduction of aliphatic nitro compounds to amines, Tetrahedron Lett., 1985, 26, 6413-6416) and subsequent treatment with K2CO3.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[N:11][C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:9]2[OH:21].Cl>N1C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[N:11][C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:9]2[OH:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc2ccc(NC(C)=O)cc2c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetyl chloride (0.6 ml.) was added to a stirred solution of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (0.932 g.) in dry pyridine (20 ml.). The solution was stirred at room temperature for 16 hours and then was poured onto a mixture of ice (100 g.) and 5N-hydrochloric acid (50 ml.). The mixture was kept at 4° C. for 4 hours, and the solid precipitate was then filtered off, washed with water (10 ml.), dried as much as possible on the filter, and recrystallised from ethanol to give ethyl 6-acetylamino-4-hydroxycinnolin-3-yl carboxylate, m.p. 280°-281° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[OH-].[Na+].[CH2:13]([O:15][CH2:16][CH2:17][OH:18])[CH3:14]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:13]([O:15][CH2:16][CH2:17][O:18][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[CH3:14]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCOCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOCCOc1ccc(C(=O)O)cn1

Procedure:
A suspension of 13.2 g (84 mmol) of 6-chloronicotinic acid, 21.2 g (0.53 mol) of powdered sodium hydroxide, 9.5 g (0.106 mol) of 2-ethoxyethanol and 2.64 g (8.2 mmol) of tetrabutylammonium bromide in 350 ml of abs. toluene is heated under reflux for 15 hours. The mixture is evaporated to dryness, and 10% strength hydrochloric acid is added to the residue, while cooling, until the mixture has pH 4. The precipitated acid is filtered off with suction.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[N:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1.[OH-].[Na+]>>[N+:6]([CH:17]1[N:16]([C:13]2[CH:12]=[CH:11][N:10]=[CH:15][CH:14]=2)[CH:20]=[CH:19][NH:18]1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: C1=CN(c2ccncc2)CN1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])C1NC=CN1c1ccncc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred solution of sulfuric acid (21 ml, 95-97%) and HNO3 (15 ml, fum.) was added at 0° C. 3-(4-pyridinyl)-1H-imidazole [CAS No. 51746-87-3] (6.36 g, 43.8 mmol). The reaction mixture was stirred at room temperature for 45 min, at 55° C. for 23 h and at 100° C. for 2 h and poured into ice-water (200 ml). Sodium hydroxide solution (32%) was added to the stirred mixture until the pH reached 5-6, the precipitated product was collected by filtration and washed with water and hexane to yield 2-nitro-3-(4-pyridinyl)-1H-imidazole (7.95 g, 95%) as a light yellow solid; mp 234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(O[Si](C)(C)C)=NC(O[Si](C)(C)C)=N2)=CC=1.Cl[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].BrCC(OCC)=O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[N:9]2[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Reactant: CCOC(=O)CCl
Agent: CCOC(=O)CBr
Agent: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccc(Cl)cc2n1
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reaction time: 13 h
Yield: 95.7 %

Procedure:
7-Chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (10 g) was treated as in Example 1 to give a concentrate containing 7-chloro-2,4-bis(trimethylsilyloxy)quinazoline. To this concentrate were added ethyl chloroacetate (21.70 g) and ethyl bromoacetate (1.70 g), and the reaction was carried out at an internal temperature of 130˜140° C. for 13 hours. This reaction mixture was cooled to ≦70° C. and worked up as in Example 4 to provide ethyl 2-(7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)acetate (13.76 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[CH3:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33]>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([CH3:28])[CH:30]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Agent: Cl
Product: Cc1cccc(C(=O)NCc2ccc(C(=N)N)cc2NCC(=O)O)c1

Procedure:
Compound 58d was reacted with 3-methylbenzoic acid and subsequently hydrogenated according to the procedure described in Example 58, to give Example 60. ESI-MS m/e 341.5 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:8][O:7]1)=[O:5])C.[OH-].[Na+:22]>O1CCCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]2([C:4]([O-:5])=[O:3])[CH2:8][O:7]2)=[CH:19][CH:18]=1.[Na+:22]
Reactant: CCOC(=O)C1(CCCCCc2ccc(Cl)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])C1(CCCCCc2ccc(Cl)cc2)CO1
Reaction time: 1 h

Procedure:
A mixture of 8.05 g of 2-[5-(4-chlorophenyl)pentyl]oxirane 2-carboxylic acid ethyl ester, 27 ml of tetrahydrofuran and 27 ml of 1 N sodium hydroxide solution is stirred for about 1 hour until a clear solution has formed. The solution is concentrated and the colorless residue is recrystallized from ethanol/diethyl ether. 6.5 g of the title compound of m.p. 136° to 142° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10](O)(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13].S(Cl)(Cl)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([NH:8][C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[OH:13])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: O=C(O)c1ccccc1O
Reactant: Nc1ccc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)nc1Cl)c1ccccc1O
Temperature: 90 °C

Procedure:
A suspension of 60.3g (0.37 mole) 2,6-dichloro-3-aminopyridine and salicylic acid 61g (0.44 mole) in 300 mL of toluene were heated to reflux for one hour. The reaction mixture was cooled at 90° C. and 34.2 ml (0.47 mole) of thionyl chloride was slowly added. After the addition the reaction mixture was refluxed for 3 hours, then cooled to room temperature. To the reaction mixture was added a solution containing 20g NaOH in 740 mL of H2O. The organic phase was separated and washed with water. The organic phase was treated with charcoal, filtered and the filtrate treated with CO2, the brownish precipitate was filtered off. Recrystallization from isopropyl alcohol gave 63.3g (60.5%) mp 179°-186° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:19][C:18]3[CH:20]=[C:21]([CH:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)[C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=4)=[CH:23][C:17]=3[N:16]=2)=[N:13][CH:14]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:19][C:18]3[CH:20]=[C:21]([CH:35]4[CH2:39][CH2:38][CH2:37][N:36]4[CH2:2][CH:1]=[O:3])[C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=4)=[CH:23][C:17]=3[N:16]=2)=[N:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccc(Br)cn4)[nH]c3cc2C2CCCN2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccc(Br)cn4)[nH]c3cc2C2CCCN2CC=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.020 ml of acetic anhydride was added to a pyridine (1 ml) solution of 43 mg of 2-(5-bromo-pyridin-2-yl)-5-(4-methanesulfonyl-phenoxy)-6-pyrrolidin-2-yl-1H-benzimidazol enantiomer A obtained in Example 342, and the reaction liquid was stirred at room temperature for 10 minutes. Aqueous saturated sodium bicarbonate solution was added to the reaction liquid, and extracted with chloroform, and the organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([NH:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:7][N:6]=1)=[O:4].[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:3]([C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][C:13]3[C:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[N:15][O:16][C:17]=3[CH3:18])=[CH:7][N:6]=2)=[O:4])[CH2:27][CH2:26]1
Reactant: COC(=O)c1cnc(NCc2c(-c3ccccc3)noc2C)cn1
Reactant: NC1CC1
Product: Cc1onc(-c2ccccc2)c1CNc1cnc(C(=O)NC2CC2)cn1
Yield: 86 %

Procedure:
As described for example 9b, 5-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyrazine-2-carboxylic acid methyl ester (650 mg, 2 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (600 mg, 86%) which was obtained as a white solid. MS: m/e=394.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[N:10]=[N:11][C:12](SCC)=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2].C(OC(N1CCC2[N:28]=[N:29]C(S)=CC=2C1)=O)C.C(Br)C>>[CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[N:10]=[N:11][C:12]([NH:28][NH2:29])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nnc(SCC)cc2C1
Reactant: CCOC(=O)N1CCc2nnc(S)cc2C1
Solvent: CCBr
Product: CCOC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
The 3-ethylmercapto-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester, required as starting material, may be obtained in a manner analogous to that described in Example 41(b), from 5,6,7,8-tetrahydro-3-mercapto-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester and ethyl bromide.