Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[S:16]1[CH:20]=[C:19]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[NH2:26])[N:18]=[CH:17]1>>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]1[CH2:12][C:13]([NH:26][C:25]1[CH:24]=[CH:23][S:22][C:21]=1[C:19]1[N:18]=[CH:17][S:16][CH:20]=1)=[O:15]
Reactant: Nc1ccsc1-c1cscn1
Reactant: O=C(O)CN1C(=O)CCc2cnccc21
Product: O=C(CN1C(=O)CCc2cnccc21)Nc1ccsc1-c1cscn1

Procedure:
The title compound was prepared from 2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetic acid (65 mg, 0.32 mmol) and 2-(thiazol-4-yl)thiophen-3-amine (57 mg, 0.32 mmol) according to protocol A. Retention time (min)=1.471, method [7], MS(ESI) 371.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 11.48 (s, 1H), 8.87 (d, J=1.8 Hz, 1H), 8.48-8.76 (m, 1H), 7.99 (d, J=5.4 Hz, 1H), 7.37 (d, J=1.8 Hz, 1H), 7.27-2.28 (m, 2H), 7.23 (d, J=5.4 Hz, 1H), 4.91 (s, 2H), 3.20-3.25 (m, 2H), 2.96-3.01 (m, 2H).
Reaction SMILES: [CH:1]1([O:9][CH2:10][CH2:11][OH:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[C:2]1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>C1COCC1>[C:14](=[O:15])([O:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[O:12][CH2:11][CH2:10][O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[C:2]1
Reactant: OCCOC1C#CCCCCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(OCCOC1C#CCCCCC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
Compound 10 (2.64 g, 15.7 mmol) and TEA (2.63 ml, 18.8 mmol 1.2 eq) dissolved in THF (0.2 M, 79 ml) were added dropwise to a stirred solution of 4-nitrophenyl chloroformate (9.49 g, 47.1 mmol, 3.0 eq) and THF (0.7 M, 22 ml) over a period of 1 h at −10° C. The reaction mixture was stirred overnight at RT and diluted with cHex (100 ml). Then cHex (100 ml) was added and the THF was removed under reduced pressure. Filtration of the reaction mixture followed by FC (cHex:EtOAc 4:1) gave compound 11 as a yellow oil (3.42 g, 10.3 mmol, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH:21]=O)=[CH:15][CH:14]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:21]([C:20]3[CH:23]=[CH:24][CH:25]=[C:18]([O:17][C:16]4[CH:26]=[CH:27][C:13]([O:12][CH3:11])=[CH:14][CH:15]=4)[CH:19]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Product: COc1ccc(Oc2cccc(C3C4=C(CC(C)(C)CC4=O)NC4=C3C(=O)CC(C)(C)C4)c2)cc1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-(4-methoxyphenoxy)-benzaldehyde in an analogous manner to that described in Example 1 to give 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9- [3-(4-methoxyphenoxy)-phenyl]-1,8(2H,5H)-acridinedione. Crystallization from ethanol/water gave a pale yellow crystalline solid of melting point 210-212° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C.[Cl:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2([CH2:60][NH2:61])[CH2:59][CH2:58]2)=[CH:53][CH:52]=1.Cl>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:61][CH2:60][C:57]2([C:54]3[CH:53]=[CH:52][C:51]([Cl:50])=[CH:56][CH:55]=3)[CH2:59][CH2:58]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: NCC1(c2ccc(Cl)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(C(=O)NCC2(c3ccc(Cl)cc3)CC2)cc1F
Temperature: 25 °C

Procedure:
To a mixture of 4-amino-3-fluorobenzoic acid (180.0 mg, 1.160 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 0.44 g, 1.2 mmol) in N,N-dimethylformamide (2 mL, 20 mmol) at 0° C. were added N,N-diisopropylethylamine (0.61 mL, 3.5 mmol) and C-[1-(4-chloro-phenyl)-cyclopropyl]-methylamine; hydrochloride (303.7 mg, 1.392 mmol). The reaction mixture was slowly warmed to rt. The reaction mixture was quenched with an equal volume of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed successively with water, aqueous lithium chloride, and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on the Isco (120 g cartridge, chloroform to 12% methanol in chloroform).
Reaction SMILES: CC(C)([O-])C.[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH3:15][O:16][N:17]([CH3:26])[C:18]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].C1(C)C=CC=CC=1>CCOCC>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([N:23]2[CH2:24][CH2:25][CH:20]([C:18]([N:17]([O:16][CH3:15])[CH3:26])=[O:19])[CH2:21][CH2:22]2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CON(C)C(=O)C1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CON(C)C(=O)C1CCN(c2ccc(Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
A flask containing 2-(2′-di-tent-butylphosphine)biphenylpalladium(II) acetate (0.927 g, 2.003 mmol) and potassium tert-butoxide (1.798 g, 16.03 mmol) was flushed with nitrogen and then charged with 4-bromochlorobenzene (3.07 g, 16.03 mmol), N-methoxy-N-methylpiperidine-4-carboxamide (2.3 g, 13.35 mmol) and anhydrous toluene (25 mL). The resulting mixture was stirred under nitrogen at 100° C. for 1.5 h. After this time, the reaction mixture was cooled to room temperature, diluted with ether (200 mL), washed with water and brine, dried over MgSO4 and concentrated to yield a residue. The residue was purified by flash chromatography using a 120 g silica gel cartridge and an eluent gradient from 10:1 Hex/EtOAc to 2:1 EtOAc/Hex. The fractions containing the product were pooled and concentrated on a rotary evaporator to the title compound (2.2 g, 7.78 mmol, 58.3% yield) as a yellow-green solid. LC-MS: (Waters Sunfire C18 4.6 mm×50 mm). 283.19, [M+H]; tR=1.79 min; 4 min gradient from 10/90/0.1 MeOH/H2O/TFA to 90/10/0.1 MeOH/H2O/TFA at 4 mL/min flow rate. 1H NMR (400 MHz, CDCl3) δ ppm 7.13-7.21 (2H, m), 6.81-6.87 (2H, m), 3.72 (3H, s), 3.69 (1H, t, J=3.30 Hz), 3.66 (1H, t, J=2.86 Hz), 3.19 (3H, s), 2.70-2.82 (3H, m), 1.82-1.94 (4H, m).
Reaction SMILES: [NH2:1][C@@:2]([C:8]1[CH:13]=[C:12]([Br:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])([CH3:7])[CH2:3][CH:4](O)[CH3:5].C([N:25]=[C:26]=[S:27])(=O)C1C=CC=CC=1.Cl>C1COCC1>[Br:14][C:12]1[C:11]([F:15])=[CH:10][C:9]([F:16])=[C:8]([C@:2]2([CH3:7])[CH2:3][CH:4]([CH3:5])[S:27][C:26]([NH2:25])=[N:1]2)[CH:13]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(O)C[C@](C)(N)c1cc(Br)c(F)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: CC1C[C@@](C)(c2cc(Br)c(F)cc2F)N=C(N)S1
Temperature: 100 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a 0° C. solution of (4S)-4-amino-4-(5-bromo-2,4-difluorophenyl)pentan-2-ol (1.3 g, 4.4 mmoles) as a mixture of diastereomers in THF (50 mL) is added benzoyl isothiocyanate (1.4 g, 1.2 mmoles) dropwise and the reaction is stirred for 1 h. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in dioxane (5 mL) and transferred to a thick-walled glass reaction vessel. To the mixture is added 5 N hydrogen chloride (75 mL, 375 mmoles) and the reaction is heated to 100° C. After 36 h, the solvent is removed under reduced pressure and the residue is dissolved in water. The water mixture is extracted with ethyl acetate. The aqueous phase is made basic with 5N NaOH and extracted with 3:1 chloroform:IPA. The chloroform: IPA phase is dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CN1C(=O)CCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)CN3CCNCC3)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), piperazine (413 mg, 6.60 mmol, 10.00 equiv), and 2.4 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-piperazin-1-yl-ethanone (26): HPLC retention time, 0.30 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 352.9, found, 353.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([N+:20]([O-:22])=[O:21])[C@H:9]([C:17]([OH:19])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:16])[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:39][O:40][C:41](=[O:59])[C@H:42]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)[NH:43][C:44](=[O:50])[C@H:45]([CH:47]([CH3:49])[CH3:48])[NH2:46]>C(Cl)Cl>[CH3:39][O:40][C:41](=[O:59])[C@H:42]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)[NH:43][C:44](=[O:50])[C@H:45]([CH:47]([CH3:49])[CH3:48])[NH:46][C:17](=[O:19])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:16])[NH2:15])[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[N+:20]([O-:22])=[O:21]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)N([C@@H](CCCNC(=N)N)C(=O)O)[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N(C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
21.5 g of t-butoxycarbonylnitroarginine is dissolved in 200 ml of methylene chloride. 15.0 ml of N-methylmorpholine is added to the solution. The solution is cooled to -70° C. 8.8 ml of isobutyl chloroformate is then added. The reaction mixture is warmed up to -15° C. and stirred for 5 minutes. The reaction mixture is again cooled to -70° C. 22.3 g of valyltyrosine methyl ester hydrochloride is added to the reaction mixture. The reaction mixture is allowed to warm to room temperature, and then is stirred for 16 hours. The reaction mixture is extracted three times with 0.5 M potassium bisulfate and once with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The residue is dissolved in 200 ml of ethyl ether. The ether solution is added to cold rapidly stirring Skellysolve B. The white precipitate is filtered and dried to afford the product t-butoxycarbonylnitroarginylvalyltyrosine methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:31])[NH:15][CH2:16][CH2:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:12]([CH2:32][O:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[NH:11][C:10]([CH3:42])=[C:9]2[C:43]([O:45]CCC#N)=[O:44])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:31])[NH:15][CH2:16][CH2:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:12]([CH2:32][O:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[NH:11][C:10]([CH3:42])=[C:9]2[C:43]([OH:45])=[O:44])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCC2CCCCC2)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCC2CCCCC2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.25 g (0.37 mmol) of 2-cyanoethyl 4-(3-chlorophenyl)-6-(2-cyclohexylethoxymethyl)-5-(3,3-diphenylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylate was dissolved in 5 ml of methanol. 0.73 ml of 1 N aqueous sodium hydroxide solution was added to the obtained solution, and they were stirred at room temperature for 2 hours. 1 N hydrochloric acid and water were added to the reaction mixture. The precipitates thus formed were taken by the filtration and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:37][S:38]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:28][CH:29]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(O)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: -20 °C
Yield: 97.1 %

Procedure:
Methyl 2-({4-[3-(4-hydroxyphenoxy)propyl]phenoxy}methyl)benzoate (0.32 g, 0.81 mmol) was dissolved in dichloromethane (10 ml) and cooled to −20° C. Triethylamine (0.123 g, 1.22 mmol) was added drop wise and methanesulfonyl chloride (0.10 g, 0.89 mmol) was added drop wise. The ice bath was removed and the mixture was wormed to room temperature. Diethyl ether (5 ml) was added and the precipitate was filtered off. The organic phase was washed with two portions of brine (5 ml) and dried (MgSO4). Removing the solvent by evaporation gave 0.37 gram of methyl 2-{[4-(3-{4-[(methylsulfonyl)oxy]phenoxy}propyl)phenoxy]methyl}benzoate (yield 97.3%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]1)=[O:4].[CH3:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1>ClCCCl.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:8][C:9]=1[N:10]([C:32]([CH:29]1[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]1)=[O:33])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NCC1CCCN(C)C1
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCCN(C)C1)C(=O)C1CCC(C)CC1
Yield: 95 %

Procedure:
3-[(1-Methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (162 mg, 0.348 mmol) was dissolved in 1,2-dichloroethane (3.0 mL) and treated with trans-4-Methyl-cyclohexanecarbonyl chloride in 1,2-dichloroethane (1.0 mL, 0.43 mmol). The solution was heated at reflux for 1 day. The solvent was then evaporated and the residue purified by silica gel column chromatography using hexanes:EtOAc as eluent to provide 3-[(4-Methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester as an oil (0.194 g, 95% yield). 1NMR (CDCl3, 400 MHz): Rotamer 65/35: 7.90 (s, 0.35H), 7.70 (d, 0.65H), 7.62-7.10 (m, 10H), 5.20-5.00 (m, 2H), 4.70 (m, 0.35H), 4.60-4.40 (m, 0.65H), 4.12 (m, 1H), 3.82 (s, 3H), 3.52 (t, 0.65H), 3.20 (t, 0.35H), 2.70 (d, 0.65H), 2.52 (t, 0.35H), 1.90 (m, 1H), 1.80-1.20 (m, 13H), 1.00-0.85 (m, 1H), 0.76 (d, 3H), 0.64 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N:16]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)=[O:5])[CH3:2].Cl.C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N:16]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34](=[NH:41])[NH2:35])=[CH:32][CH:33]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1c(COc2ccc(C#N)cc2)nc2ccc(N(CCN(C)C)S(C)(=O)=O)cc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)Cn1c(COc2ccc(C(=N)N)cc2)nc2ccc(N(CCN(C)C)S(C)(=O)=O)cc21

Procedure:
Prepared analogously to Example 1e from 1-ethoxycarbonylmethyl-2-[(4-cyanophenyl)-oxymethyl]-6-[N-(2-dimethylaminoethyl)-methanesulphonylamino]-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2cccnc2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cccnc3)CC2)C1

Procedure:
The title compound was prepared as yellow solid using the procedure described in Step E of Example 1 from reductive amination of 4-Hydroxy-4-pyridin-3-yl-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:33][C:32]5[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN2CCn3c(cc4cc(OC5CCN(C(C)C)CC5)ccc43)C2=O)cc1
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 4-methoxybenzyl chloride, to give the desired product as a white solid (50%).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][CH2:4][NH:3]1.N[CH2:9][C@@H:10]1CC[CH2:12][N:11]1CC.C(=O)C>>[CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:9][CH2:10][NH:11][CH3:12]
Reactant: CCN1CCC[C@H]1CN
Reactant: CC1(C)CCCN1
Agent: CC=O
Product: CNCCN1CCCC1(C)C

Procedure:
By using 2,2-dimethylpyrrolidine (1.0 g) as a starting material, the title compound (1.25 g) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[C:12]([C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([OH:14])=[O:13]>O.CC(C)=O>[CH2:11]([N:18]1[CH2:19][CH2:20][C:15]([C:12]([OH:14])=[O:13])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:17]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
106 ml of a 30 % NAOH solution is added to a suspension of 100 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate in 600 ml of water, then the thus obtained solution is cooled to 5° C., a solution of 47.6 g of bromide benzyl in 100 ml of acetone is added dropwise and left under stirring for 1 hour while the temperature being allowed to rise to RiT. The acetone is evaporated under vacum, and the pH of the remaining aqueous phase is brought to 9.5 by adding concentrated aqueous solution of HCl, then the pH is adjusted to 8.5 by adding a 2N HCl solution. The precipitate formed is wrung and washed with water and then with acetone to give 70 g of the expected compound, M.p.=286° C.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:31]([CH3:39])([CH2:32][CH2:33][C:34]=32)[C@@H:18]([C@H:19]([CH3:30])[CH2:20][CH2:21][CH2:22][NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH:16]=4)[C:10]1([CH3:41])[CH3:40])(C(C)(C)C)(C)C.C(O)C.Cl>>[CH3:41][C:10]1([CH3:40])[C@@H:9]([OH:8])[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@H:11]1[CH2:12][CH2:13][C:14]1[C:15]3[C@:31]([CH3:39])([CH2:32][CH2:33][C:34]=12)[C@@H:18]([C@H:19]([CH3:30])[CH2:20][CH2:21][CH2:22][NH:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:17][CH:16]=3
Reactant: C[C@H](CCCNc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: Cl
Solvent: CCO
Product: C[C@H](CCCNc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Yield: 66.1 %

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-24-phenylamino-5α-chola-8,14-dien (100 mg) is hydrolysed with ethanol/HCl at 50° C. Aqueous work-up and crystallization from ethanol gives the title compound (53 mg). Melting point: 178-180° C. 1H-NMR (CDCl3, 300 MHz)): δ=7.19 (2H, t); 6.7 (1H, t); 6.63 (2H, d); 5.36 (1H, s); 3.6 (1H, s); 3.26 (1H, m); 3.1 (2H, m). MS: Calculated: 461.7. Found: 461.3.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:21])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10]([Cl:20])=[N:9][CH:8]=1.Cl>O1CCCC1.O>[Cl:20][C:10]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:12][C:7]([C:6]([OH:21])=[O:5])=[CH:8][N:9]=1
Reactant: COC(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
Lithiumhydroxide monohydrate (2.41 g, 57 mmol) was added to a solution of 6-chloro-5-(4-chloro-phenyl)-nicotinic acid methyl ester (8.1 g, 29 mmol) in tetrahydrofuran (120 mL) and water (34 mL) under nitrogen at room temperature. The reaction mixture was stirred for 20 h at room temperature, poured onto ice/water (200 g), acidified with 1 N HCl (120 mL) and the whole was extracted with ethyl acetate (250 mL). The water phase was extracted twice with ethylacetate (2×200 mL), organic phases were combined, dried over MgSO4 and concentrated in vacuo. 6-chloro-5-(4-chloro-phenyl)-nicotinic acid was isolated as a colorless solid and used without further purification; 7.30 g (94% yield). m/z (ISP−): 266.1 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:17])[NH:15][NH2:16])=[N:6]1.[O:22]=[CH:23][C:24](OCC)=O>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][CH:24]=[C:23]([OH:22])[N:17]=2)=[N:6]1
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: CCOC(=O)C=O
Solvent: CCO
Product: Oc1cnnc(-c2nn(Cc3ccccc3F)c3ncccc23)n1

Procedure:
22.000 g (purity 68%, approx. 52.621 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidohydrazide in 220 ml of ethanol were initially introduced, admixed dropwise with 18.265 (89.455 mmol) of ethyl oxoacetate (50% strength solution in toluene) and heated under reflux overnight. The resulting suspension was concentrated on a rotary evaporator and stirred with diethyl ether. The solid was filtered off with suction and dried under high vacuum. Further purification was effected by chromatography on silica gel (mobile phase: dichloromethane/methanol, gradient 30:1→10:1). This gave 12.07 g of the target compound (purity 69%; 49% of theory).