Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]1.Cl>ClCCl.C(N(CC)CC)C>[O:11]=[CH:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:9][CH2:5][C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:23])[CH2:19][CH2:20]1
Reactant: O=C(O)N1CCC(CCCO)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
0.81 ml of dimethylsulphoxide in solution in 10 ml of dichloromethane (DCM) is cooled to −50° C. and 0.42 ml (4.8 mM) of oxalyl chloride in solution in 1.5 ml of DCM are added. The mixture is agitated for 10 minutes at −60° C. are then, at this temperature, 1.21 g (4.4 mM) of the benzyl ester of 4-(3-hydroxypropyl)piperidinecarboxylic acid in solution in 6 ml of DCM are added dropwise. The reaction mixture is agitated for 30 minutes at −50° C. and 3 ml of triethylamine are then added dropwise and the temperature is allowed to rise up to ambient temperature in 2 hours. The mixture is hydrolysed on 25 ml of N hydrochloric acid and extracted with DCM. The organic phase is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The crude product is purified by silica gel chromatography in eluting with the aid of a cyclohexane/ethyl acetate mixture (75/25; v/v). The product sought after is thus obtained as a yellow oil (yield=83%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:8].O.[OH-].[Na+]>O1CCCC1>[CH2:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:7][NH2:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CCCCNCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCCCNCc1ccccc1
Yield: 57.3 %

Procedure:
To a suspension of 1.1 g of lithium aluminum hydride in 50 ml of tetrahydrofuran was added slowly 2.9 g of N-(3-cyanopropyl)benzylamine (obtained in Reference Example 4) at room temperature. The reaction mixture was heated gently under reflux for 15 minutes and then allowed to cool. To the mixture was added dropwise and carefully 2.2 ml of water and then 1.8 ml of 10% aqueous sodium hydroxide. The resultant precipitate was filtered off, the filtrate was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give 1.7 g of N-benzyl-1,4-butanediamine as a colorless oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([CH3:20])[CH:14]=1>>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:3](=[O:5])[CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8])=[C:15]([CH3:20])[CH:14]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(Br)ccc1N
Product: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Temperature: 160 °C
Yield: 62.5 %

Procedure:
Into a 500 milliliter four-necked round-bottom reaction flask equipped with a mechanical stirrer, Dean-Stark trap/condenser, thermometer and heating mantle was added 320 grams (2.0 mol) of diethyl malonate and 37.2 grams (0.2 mol) of 4-bromo-2-methylaniline. The resulting mixture was heated at a temperature of 160° C. for a period of four hours and then cooled to a temperature of about 0° C. to form a precipitate. After filtering on a fritted glass funnel, the wet-cake was washed with heptane and air dried to give 37.6 grams (0.125 mol) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate. Liquid chromatographic analysis indicated 97 percent purity by comparison with an authenic sample of pure material. NMR analysis of the product indicated the following: 'H NMR (CDCl3) δ9.52 (1H, bs), 8.02 (1H, d, J=9 Hz), 7.2-7.5 (2H, m), 4.30 (2H, q, J=7 Hz), 3.50 (2H, s), 2.30 (3H, s), 1.30 (3H, t, J=7 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH:15][C:16]2[N:17]=[CH:18][C:19]3[N:24]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:22][C:20]=3[N:21]=2)[CH:9]=1)(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH:15][C:16]2[N:17]=[CH:18][C:19]3[N:24]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:22][C:20]=3[N:21]=2)[CH:9]=1
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)OC(C)(C)C)ccc3C)nc2s1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2cnc(Nc3cc(N)ccc3C)nc2s1
Yield: 82.6 %

Procedure:
A solution of tert-butyl(3-{[2-(acetylamino)[1,3]thiazolo[5,4-d]pyrimidin-5-yl]amino}-4-methylphenyl)carbamate (1.27 g, 3.06 mmol) and anisole (2 mL) in trifluoroacetic acid (20 mL) was stirred at 0° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture (1:1, 50 mL, 2×10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (795 mg, 83%) as a pale-green solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]2[C:3]=1[CH2:4][CH:5]([CH3:15])[CH2:6][C:7]2=[O:14].B(Br)(Br)Br.O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][CH:5]([CH3:15])[CH2:6][C:7]2=[O:14]
Reactant: COc1ccc(Br)c2c1C(=O)CC(C)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC1CC(=O)c2c(O)ccc(Br)c2C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of 5-bromo-8-methoxy-3-methyl-1,2,3,4-tetrahydronaphthalen-1-one (32.2 g 0.12 mol) in DCM (400 mL) at 0° C. was added boron tribromide (119 mL of a 1.0 M solution in DCM, 0.12 mol) dropwise. The mixture was stirred at 5° C. for 1 h then water (50 mL) was added cautiously. The mixture was washed with water (3×200 mL) then the organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with hexane: DCM (100:0-1:1), to afford the phenol (23.5 g, 77%). 1H NMR (250 MHz, CDCl3) δ 1.18 (3H, d, J=6.1 Hz), 2.22-2.55 (3H, m), 2.69-2.77 (1H, m), 3.14-3.23 (1H, m), 6.74 (1H, d, J=8.9 Hz), 7.59 (1H, d, J=8.9 Hz), 12.54 (1H, s)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([CH3:37])[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:34]5[CH:33]=[N:32][C:31]([O:30][CH3:29])=[CH:36][C:35]=5[CH3:37])[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COc1cc(C)c(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 120 °C
Yield: 24 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol), 2-Methoxy-4-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (298 mg, 1.2 mmol), Cs2CO3 (650 mg, 2.0 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol) and CH3CN—H2O (1:1, 4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 120° C. for 20 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to afford 337 (120.8 mg, yield: 24%). 1HNMR (DMSO-d6, 400 MHz): δ8.29 (s, 1H), 8.20 (s, 1H), 7.92-7.81 (m, 1H), 7.70 (t, J=2.4 Hz, 1H), 7.51-7.41 (m, 3H), 7.24 (s, 2H), 6.75 (s, 1H), 4.31 (s, 2H), 3.89 (s, 3H), 3.19 (s, 2H), 2.32 (s, 3H). ESI-MS: m/z=504 [M+H+]
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([Mg]Br)[CH3:11].B(F)(F)F.CCOCC.Cl>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1COCC1.C(OCC)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2([NH2:7])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc(I)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC1(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
Titanium(IV) isopropoxide (7.1 mL) was added to a diethyl ether (0.14 L) solution of 4-iodobenzonitrile (5.0 g) and, with the internal temperature being kept at −60° C. or lower, a THF solution (53 mL) of 0.90 mol/L ethylmagnesium bromide was added dropwise. After the mixture was stirred for 1 hour at room temperature, boron trifluoride diethyl etherate (5.4 mL) was added, and the mixture was stirred for 3 hours at room temperature. Upon addition of 1.0 mol/L hydrochloric acid (65 mL), the aqueous layer was washed with diethyl ether. A 1.0 mol/L sodium hydroxide aqueous solution was added to the washed aqueous layer to bring it to pH 9. The precipitate was filtered out using Celite, and the filtrate was extracted with ethyl acetate. The extract was dried over magnesium sulfate, whereafter the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=50/50→1/99) to obtain 1-(4-iodophenyl)cyclopropylamine (light yellow solid) (1.3 g, 23%).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([Cl:21])=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.Cl.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[ClH:21].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([CH:37]1[CH2:42][CH2:41][N:40]([C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([NH:14][C:8]3[C:7]4[C:12](=[CH:13][C:4]([C:3]([F:25])([F:24])[F:2])=[CH:5][CH:6]=4)[N:11]=[CH:10][CH:9]=3)=[CH:16][CH:17]=2)[CH2:39][CH2:38]1)(=[O:35])=[O:36]
Reactant: O=C(Cl)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Reactant: O=S(=O)(c1ccccc1F)C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCC(S(=O)(=O)c2ccccc2F)CC1
Yield: 46.8 %

Procedure:
(B 5) 4-[[7-(Trifluoromethyl)-4-quinolyl]amino]benzoyl chloride hydrochloride (65.20 g) was added slowly to a stirred mixture of 4-[(2-fluorophenyl)sulfonyl]piperidine hydrochloride (47.0 g) and triethylamine (117.2 ml) in dry methylene chloride (1.01 l) at room temperature. The resultant mixture was stirred at the same temperature for 1 hour and under ice cooling for 0.5 hours. The precipitated powder was collected by filtration, washed with a mixture of methylene chloride and water, and suspended in a mixture of chloroform and methanol. Excess methanolic hydrochloric acid was added to the suspension and the resulting solution was concentrated in vacuo to give an oil. The oil was triturated in a mixture of ethyl acetate and ethanol to give powdery 4-[(2-fluorophenyl)sulfonyl]-1-[4-[[7-(trifluoromethyl)-4-quinolyl]amino]benzoyl]piperidine hydrochloride (46.73 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][N:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]3.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][N:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]3)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c3c1c(=O)c(C(=O)O)cn3CCC2
Product: CC(=O)Nc1ccc2c3c1c(=O)c(C(=O)O)cn3CCC2

Procedure:
Using the method of Example 49, 10-amino-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid is reacted with acetic anhydride to provide 10-acetamido-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. >300° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][CH:12]([CH2:17][O:18][CH3:19])[CH2:13][CH2:14][O:15][CH3:16])[CH:5]=[C:4]([CH3:20])[N:3]=1.C(O)(=O)C>CO.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH3:20])=[CH:5][C:6]=1[NH:11][C@H:12]([CH2:17][O:18][CH3:19])[CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCC(COC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: COCC[C@@H](COC)Nc1cc(C)nc(Cl)c1N

Procedure:
2-Chloro-6-methyl-3-nitro-N-(1-methoxymethyl-3-methoxypropyl)pyridin-4-amine (˜16.82 mmol) was heated at reflux with Fe powder (10 g) in methanol (120 mL) in the presence of glacial acetic acid (10 mL) for 2 h. Then the iron was filtered through celite, the celite was washed with methanol(80 mL) and the filtrate was stripped in vacuo. The residue was dissolved in 10% HCl (120 mL) and EtOAc was added (160 mL). The mixture was neutralized with solid NaHCO3 and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4) and stripped in vacuo (4.1 g). NMR(CDCl3)d 6.4 (s, 1H), 5.2-5.35 (br s, 1H), 3.70-3.80 (m, 1H), 3.2-3.8 (m, 6H), 3.38 (s, 3H), 3.33 (s, 3H), 2.42 (s, 3H), 1.8-2.0 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([OH:24])=O)=[N:16][C:12]=3[CH:11]=[C:10]([C:33]#[N:34])[N:9]=2)[CH:5]=[N:6][CH:7]=1.CCCP(=O)=O.[CH3:41][NH:42][CH2:43][CH3:44]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([N:42]([CH2:43][CH3:44])[CH3:41])=[O:24])=[N:16][C:12]=3[CH:11]=[C:10]([C:33]#[N:34])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(=O)O)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CCNC
Agent: CCCP(=O)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C)C(=O)[C@@H]1CCCN1c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a reaction vessel was added the crude residue of (S)-1-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)pyrrolidine-2-carboxylic acid (0.030 g, 0.063 mmol), propylphosphonic anhydride (0.10 mL, 50% w/w in DMF), and N-methylethanamine (0.0037 g, 0.063 mmol) suspended in DMF (0.5 mL). The reaction was stirred at ambient temperature for 6 hours. The reaction was diluted with H2O (2.0 mL) and was extracted with EtOAc (2×5 mL). The combined organics were concentrated in vacuo to afford (S)-1-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-N-ethyl-N-methylpyrrolidine-2-carboxamide as a crude residue. MS ESI calc'd. for C28H34ClN7O [M+H]+ 520. found 520.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15]/[C:16](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].[ClH:32]>C(O)C.ClCCl>[ClH:32].[C:24]1(/[C:16](=[CH:17]\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOC/C(=C/c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOC/C(=C/c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above ester (1.45 g, 3.7 mmol) was dissolved in absolute ethanol (15 ml) and 4N sodium hydroxide (1.9 ml) was added. After stirring at ambient temperature for 4 h the mixture was diluted with dichloromethane (300 ml), cooled to 0° C. and 4N hydrochloric acid (4 ml) was added. The mixture was dried (Na2SO4) and the solvent evaporated in vacuo. The residue was re-evaporated with acetone, suspended in acetone (10 ml), the precipitate collected and dried in the air. This afforded 1.2 g of the title compound as a solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22]([OH:24])=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCOCC1.[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl>[C:45]1([NH:44][C:22](=[O:24])[CH2:21][CH2:20][C@H:19]([C@@H:18]2[C@:26]3([CH3:34])[C:15]([C:14]4[CH2:13][CH2:12][C@@H:11]5[C@:30]([C:29]=4[CH2:28][CH2:27]3)([CH3:33])[CH2:31][CH2:32][C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C:10]5([CH3:36])[CH3:35])=[CH:16][CH2:17]2)[CH3:25])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: Nc1ccccc1
Reactant: C[C@H](CCC(=O)O)[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
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](CCC(=O)Nc1ccccc1)[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
Temperature: -15 °C
Reaction time: 8 h

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid (0.50 g) is dissolved in 15 ml of dry dichloromethane. After cooling to −15° C., 0.188 ml of N-methylmorpholine and 0.153 ml of isobutylchloroformiate is added and the mixture is stirred at −15° C. for 20 minutes, whereupon 0.44 ml of aniline is added. The mixture is stirred overnight and the temperature is slowly elevated to room temperature. After aqueous work-up and crystallization from methanol, 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid-N-phenyl amide (0.431 g) is obtained. H-NMR (CDCl3, 400 MHz): δ=7.53 (2H, d); 7.34 (2H, t); 7.17 (1H, s); 7.12 (1H, t); 5.35 (1H, s); 3.21 (1H, m); 0.9 (9H, s); 0.04 (6H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]1([CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[C:18]1([CH2:24][CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:2][C:3]3[NH:4][C:5]4[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=4[N:7]=3)[CH2:30][CH2:31]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CCC2CCNCC2)cc1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CCC2CCN(Cc3nc4ccccc4[nH]3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.5 %

Procedure:
2-(Chloromethyl)benzimidazole (448 mg, 2.64 mmol) and potassium carbonate (729 mg, 5.28 mmol) were added to a solution of 4-(2-phenylethyl)piperidine (500 mg, 2.64 mmol) in dry DMF (20 ml) under a nitrogen atmosphere and the mixture stirred at room temperature for 20 hours. The reaction was diluted with water (200 ml) and extracted with ethyl acetate (3×100 ml), the combined organic layers were washed with water (25 ml) and brine (50 ml), dried (MgSO4) and evaporated in vacuo to give a brown oil which was triturated with toluene and recrystallised from methanol to give the title compound as a sandy solid (97.3 mg, 12%), m.p. 170° C.; (Found: C, 78.38; H, 7.79; N, 12.93. C21H25N3.0.1 H2O requires C, 78.51; H, 7.91; N, 13.08%); δH (DMSO-d6) 1.22 (3H, m, piperidinyl H and CH2CH2Ph), 1.50 (2H, m, piperidinyl CH2), 1.67 (2H, m, piperidinyl CH2), 2.01 (2H, m, piperidinyl CH2), 2.56-2.60 (2H, m, piperidinyl CH2), 2.83 (2H, d, J 10.8Hz, CH2 -Ph), 3.67 (2H, s, N-CH2Ar), 7.12-7.19 (5H, m, ArH), 7.24-7.28 (2H, m, ArH), 7.42 (1H, d, J 7.3 Hz, ArH), 7.53 (1H, d, 3 7.3Hz, ArH), and 12.20 (1H, brs, NH); m/z (CI+, NH3) 320 (M+1)+.
Reaction SMILES: [NH:1]1[C:9](=[O:10])[C:8]2[C:4]([N:5]=[CH:6][N:7]=2)=[N:3][C:2]1=[N:11][NH2:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][N:24]=[C:23]([CH2:26][CH2:27][CH:28]=O)[N:22]=2)=[CH:17][CH:16]=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[O:25][N:24]=[C:23]([CH2:26][CH2:27][C:28]3[N:1]4[C:9](=[O:10])[C:8]5[NH:7][CH:6]=[N:5][C:4]=5[N:3]([CH2:17][CH2:16][CH2:15][CH2:20][CH3:19])[C:2]4=[N:11][N:12]=3)[N:22]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(-c2nc(CCC=O)no2)cc1
Reactant: NN=C1N=C2N=CN=C2C(=O)N1
Solvent: CCO
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCc3noc(-c4ccc(OC)cc4)n3)nnc12
Yield: 64.3 %

Procedure:
A mixture of 1H-purine-2,6-dione 2-hydrazone (680 mg, 2.88 mmol) and 3-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]propanal (900 mg, 3.88 mol) in ethanol (20 mL) was refluxed for 4 hours. The reaction mixture was concentrated and the residue was mixed with acetic acid (10 mL). The resulting mixture was refluxed for 3 hours. The reaction mixture was concentrated and then diluted with water and extracted with EtOAc (3×). The combined organic layers was dried over Na2SO4, filtered, concentrated and purified by preparative LCMS to give the desired product (830 mg, 64% yield). LCMS calculated for C22H25N8O3 (M+H): 449.2. Found: 449.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27](O)=[O:28])=[CH:25][N:26]=3)[CH:23]=2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[CH3:30][C:31]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH2:33][CH2:32]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]([NH:37][S:34]([C:31]4([CH3:30])[CH2:33][CH2:32]4)(=[O:36])=[O:35])=[O:28])=[CH:25][N:26]=3)[CH:23]=2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: O=C(O)c1cnc2ccc(N3CCCCC3c3cc(F)cc4c3OCCO4)cn12
Product: CC1(S(=O)(=O)NC(=O)c2cnc3ccc(N4CCCCC4c4cc(F)cc5c4OCCO5)cn23)CC1

Procedure:
The title compound was prepared by the method similar to that of Example 31 employing 6-(2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (Int 42) and 1-Methylcyclopropane-1-sulfonamide (int-50) to afford an enantiomeric mixture, which was purified by chiral chromatography employing CHIRALPAK AD-H column with n-HEXANE:ETHANOL, 60:40 Isocratic solution as eluent. MS (ESI): m/z 515.2 (M+H); 1H NMR (600 MHz, DMSO-d6) δ 11.88 (1H, s), 8.74 (1H, s), 8.55 (1H, s), 7.65-7.64 (1H, d, J=10.4 Hz), 7.52-7.50 (1H, d, J=10.4 Hz), 6.51-6.45 (2H, m), 4.45-4.42 (3H, m), 4.30-4.22 (2H, m), 3.64-3.62 (1H, d), 2.79-2.73 (1H, m), 1.90-1.78 (4H, m), 1.57-1.53 (8H, m), 1.23-1.03 (2H, m) ppm.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-])=O)=[CH:4][C:3]=1[C:15]([O:17]C1C=CC=CC=1)=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>[OH-].[Na+].COCCOCCOC>[NH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:15](=[O:17])[NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](=[O:33])(=[O:32])[NH2:34])=[CH:27][CH:26]=2)[CH:4]=1
Reactant: O=C(Oc1ccccc1)c1cc([N+](=O)[O-])c2ccccc2c1O
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: Nc1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2)c(O)c2ccccc12
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
A mixture composed of 30.9 g (0.1 mol) of phenyl 1-hydroxy-4-nitro-2-naphthoate, 17.2 g of p-aminobenzenesulfonamide and 200 ml of diethylene glycol dimethyl ether was heated at 160° C. for 3 hours. After cooling, the separated yellow crystals were filtered off. Yield: 19 g. 7.74 g (0.02 mol) of the resulting yellow crystals were dissolved in 100 ml of 10% sodium hydroxide. Then 40 g of sodium hydrosulfite was added at 50° to 60° C. thereto. After stirring at the same temperature for 30 minutes, the solution was allowed to cool and neutralized with diluted hydrochloric acid. The resulting light yellow precipitate of (4-a) was filtered off. Yield: 5.3 g