Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: COc1cc(Cl)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Cl)nc(OCc2ccccc2)n1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
4-Chloro-6-methoxy-2-(methylsulfonyl)pyrimidine (Compound III-29) (0.80 g, 0. 0036 mol) and benzyl alcohol (Compound II-64) (0.39 g, 0.0036 mol) were dissolved in toluene (10 ml), and then 60% sodium hydride (0.16 g, 0.0036×1.1 mol) was added while cooling with ice. After stirred for one night at room temperature, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and thereafter, the solvent was distilled off to afford a crude product (0.92 g), which was then purified on silica gel column chromatography to obtain the compound (I-346) as an oily product.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:18])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1.O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:12]([N:18]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1
Reactant: NCC1CCCO1
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC1CCCO1

Procedure:
19.8 g (134 mmol) of phthalic anhydride were dissolved in 500 ml of chloroform. To the resultant solution, 10 g (99 mmol) of tetrahydrofurfurylamine were added with stirring. The resultant mixture was subjected to a reflux overnight while the reactant water yielded was distilled off. The thus obtained reaction mixture was allowed to cool and then was poured into 300 ml of aqueous solution of saturated sodium hydrogencarbonate. Thereafter, an organic solvent layer was separated from the reaction mixture. The residual water layer was subjected to an extraction twice with chloroform and the extract thus obtained was combined with the organic solvent layer which was previously separated.
Reaction SMILES: C(OCC[O:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18]C(=O)C)=[C:11](Br)[CH:10]=1)(=O)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[OH:18][CH2:17][CH2:16][O:15][C:12]1[C:11]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=2)=[CH:10][C:9]([C:8]([OH:7])=[O:23])=[CH:14][CH:13]=1
Reactant: CC(=O)OCCOC(=O)c1ccc(OCCOC(C)=O)c(Br)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: O=C(O)c1ccc(OCCO)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The compound of step 1 was coupled to 3-trifluoromethyl-phenylboronic acid in analogy to step 3 of example 92, the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield 6-(2-Hydroxy-ethoxy)-3′-trifluoromethyl-biphenyl-3-carboxylic acid. This intermediate was coupled to trans-1-amino-4-ethylcyclohexanecarboxylic acid methylester hydrochloride in analogy to step 1 of example 3, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=2[N:6]=[CH:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12>CCCCCC.CCOC(C)=O>[C:47]1(=[O:57])[N:51]([CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=3[N:6]=[CH:5]2)[C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12
Reactant: O=[N+]([O-])c1ccc2c(c1)ncn2CCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCn1cnc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 1-(2-hydroxyethyl)-5-nitrobenzimidazole (0.27 g, 1.3 mmol) was added triphenylphosphine (0.38 g, 1.4 mmol), DEAD (0.25 ml, 1.4 mmol) and phthalimide (0.21 g, 1.4 mmol) in a portion and resulting mixture was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo, yielding an oil which was subjected to column chromatography (40% Hexane/EtOAc) to provide 0.36 g (1.1 mmol, 82%) of 1-(2-phthalimidylethyl)-5-nitrobenzimidazole. The nitrobenzimidazole was subsequently subjected to hydrogenation, bromination and coupling with ISA to produce 0.41 g of 1-(2-phthalimidylethyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole which was refluxed with 0.3 ml of hydrazine in 20 ml of MeOH for 0.5 h to yield the desired product (0.31 g, 0.96 mmol, 68% overall). The product obtained was converted to the fumarate salt and recrystallized from isopropanol to afford 0.21 g (24%) of the product as a white foamy solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25]>O>[CH2:1]([N:3]([CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1)[C:24](=[O:25])[CH2:23][Cl:22])[CH3:2]
Reactant: CCNCC1OCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCN(CC1OCCO1)C(=O)CCl

Procedure:
N-Ethyl-N-(1,3-dioxolan-2-ylmethyl)amine (50 grams), benzene (100 ml), water (100 ml) and sodium carbonate (5.0 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (3 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-ethyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][CH:13]([C:16](O)=O)[CH2:12][CH2:11]2)=[CH:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:41][CH2:42][N:43]([CH2:16][C@H:13]2[CH2:14][CH2:15][C@H:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:11][CH2:12]2)[CH2:44][CH2:45]1
Reactant: O=C(O)C1CCC(c2c[nH]c3ccccc23)CC1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(N2CCN(C[C@H]3CC[C@H](c4c[nH]c5ccccc54)CC3)CC2)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-(1H-3-indolyl)-cyclohexanecarboxylic acid (1.60 g, 6.57 mmol) and methylene chloride (30 mL) is treated with triethylamine (1.53 mL, 10.97 mmol) and the resulting solution is cooled to 0° C. Isobutyl chloroformate (0.93 mL, 7.15 mmol) is added and the reaction is stirred at 0° C. for 10 minutes. A solution of 1-(2-pyridinyl)piperazine (1.18 g, 7.23 mmol) in methylene chloride is added and the reaction is then stirred at ambient temperature for 18 hours. A saturated solution of sodium bicarbonate (20 mL) is added and the organic phase is separated. The aqueous phase is extracted with two 40 mL portions of methylene chloride and the combined organic extracts are dried with sodium sulfate, and evaporated. The residue is chromatographed on silica gel (2% methanol in chloroform) and 2 main fractions are isolated. The first fraction consisted of trans 1-({4-[1H-3-indolyl]cyclohexyl}carboxyl)-4-(2-pyridinyl)piperazine and the second fraction consisted of the corresponding cis isomer. The resulting trans amide is reduced by the method described in Example 1 to give trans 3-[4-[4-(2-pyridinyl)-1-piperazinylmethyl]cyclohexyl]-1H-indole (Example 15); m/e 374.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12](I)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32]1([CH3:50])[C:36]2[CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=[CH:40][C:35]=2[O:34][CH2:33]1>>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:38]2[CH:39]=[CH:40][C:35]3[O:34][CH2:33][C:32]([CH3:31])([CH3:50])[C:36]=3[CH:37]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)COc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Product: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(-c2ccc3c(c2)C(C)(C)CO3)c1[C@H](OC(C)(C)C)C(=O)O
Yield: 84 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 87 from (S)-methyl 2-(tert-butoxy)-2-(1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-(3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (WO2009/062285) to afford the title compound (76 mg, 84%) after purification by reverse phase HPLC. 1H NMR (400 MHz, DMSO-d6, VT) δ ppm 7.49-7.19 (m, 5 H), 7.16 (d, J=2.0 Hz, 1 H), 6.92 (d, J=8.2 Hz, 1 H), 6.10 (br. s., 1 H), 5.42 (d, J=2.7 Hz, 2 H), 5.31 (s, 1 H), 4.32 (s, 2 H), 2.66-2.59 (s, 3 H), 1.42-1.32 (br. s., 3 H), 1.27 (br. s., 3H), 0.84 (s, 9 H); LC/MS ES+=535.52 (M+1).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][CH:14]([F:55])[C:15]1[N:19]([C:20]2[N:25]=[C:24]([NH:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:23]([N+:40]([O-])=O)=[C:22]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:21]=2)[C:18]2[CH:49]=[CH:50][CH:51]=[C:52]([O:53][CH3:54])[C:17]=2[N:16]=1>O1CCOCC1.O>[F:13][CH:14]([F:55])[C:15]1[N:19]([C:20]2[N:25]=[C:24]3[C:23]([NH:40][C:1](=[O:2])[N:26]3[CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[C:22]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:21]=2)[C:18]2[CH:49]=[CH:50][CH:51]=[C:52]([O:53][CH3:54])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c(N2CCOCC2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
1,1′-Carbonyldiimidazole (689 mg, 4.25 mmol) was added to a solution of the above amine (244 mg, 0.425 mmol) in 1,4-dioxane (25 mL) and the mixture was refluxed under nitrogen for 4.5 hrs. Additional 1,1′-carbonyldiimidazole (689 mg, 4.25 mmol) was added, and the mixture refluxed for additional 17.5 hrs. The mixture was cooled to room temperature and diluted with water. The resulting precipitate was collected by filtration, washed with H2O, and dried. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 97:3), gave tert-butyl 4-[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-1-piperidinecarboxylate (176 mg, 69%): mp (CH2Cl2/i-Pr2O) 269-272° C.; 1H NMR (CDCl3) δ 10.94 (br s, 1H), 7.73 (dd, J=8.3, 0.3 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 7.36 (t, JHF=53.6 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.49 (tt, J=12.1, 4.1 Hz, 1H), 4.38 (br s, 2H), 4.06 (s, 3H), 3.89 (dd, J=5.6, 3.6 Hz, 4H), 3.82 (dd, J=5.6, 3.7 Hz, 4H), 2.85 (m, 2H), 2.56 (m, 2H), 1.83 (d, J=11.0 Hz, 2H), 1.48 (s, 9H); Anal. Calcd. for C28H34F2N8O5.0.1 i-Pr2O: C, 56.2; H, 5.8; N, 18.3. Found: C, 56.2; H, 5.90; N, 18.0%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32]OS(C5C=CC(C)=CC=5)(=O)=O)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:45])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1.[CH3:54][NH:55][CH3:56]>C(N(CC)CC)C>[CH3:54][N:55]([CH3:56])[CH2:32][CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]2[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[O:45])[CH2:19][CH:18]2[O:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]3[O:9][CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=3[CH:12]=2)=[CH:25][CH:26]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCOS(=O)(=O)c4ccc(C)cc4)cc3)cc21
Reactant: CNC
Solvent: CCN(CC)CC
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCN(C)C)cc3)cc21

Procedure:
A solution of 0.193 g of benzyl 3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[2-(toluene-4-sulphonyloxy)ethoxy]phenyl}piperidine-1-carboxylate (Example 267c), 0.131 g of triethylamine and 1.769 g of dimethylamine (33% in ethanol) is stirred at room temperature for 3 days and then concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (200:10:1 dichloromethane-methanol-conc. ammonia); Rt=4.40.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:12]=[C:13]([C:25]#[N:26])[C:14]([C:23]#[N:24])=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5]1)([CH3:3])[CH3:2].CC[OH:29]>OO.O.O.O.[O-][Mo]([O-])(=O)=O.[Na+].[Na+]>[C:25]([C:13]1[C:14]([C:23]([NH2:24])=[O:29])=[N:15][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[N:12]=1)#[N:26]
Reactant: CCO
Reactant: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2)ccc1=O
Agent: O=[Mo](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(C)n1nc(-c2nc(C#N)c(C(N)=O)nc2-c2ccccc2)ccc1=O
Temperature: 42.5 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2,3-pyrazinedicarbonitrile (343 mg) in EtOH (10 ml) was dropwise added a solution of sodium molybdate dihydrate (12.1 mg) in a mixture of 30% hydrogen peroxide solution in water (0.57 ml) and EtOH (1.5 ml) and the mixture was stirred at 40-45° C. for 3 hours. After ice-cooling, a precipitate was collected by filtration to give 3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2-pyrazinecarboxamide as a solid (171 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>CCO>[N+:8]([C:7]1[C:2]([NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Yield: 74.9 %

Procedure:
To a solution of 2-chloro-3-nitropyridine (25.3 g) in EtOH (300 mL) were added ethyl 2-aminoacetate hydrochloride (28.7 g) and triethylamine (28.9 mL) at room temperature, and the mixture was refluxed for 1 day. The mixture was concentrated under reduced pressure. The residual crystals were removed by filtration and washed with AcOEt. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 20%-70% AcOEt in hexane). The residual crystals were removed by filtration and washed with IPE. The filtrate was concentrated under reduced pressure to give the title compound (26.9 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([O:9][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The product from Example 11 (50.0 g; 178 mmol) is dissolved in anhydrous pyridine (910 ml). Methanesulphonyl chloride (18.6 ml; 241 mmol) is added dropwise while cooling in ice. Subsequently, the solution is stirred for 2.5 h during which it is allowed to warm to room temperature. The solution is then diluted with dichloromethane (3.6 l) and extracted twice by shaking with a 10% solution of sodium hydrogen carbonate (1.1 l on each occasion). The organic phase is dried (magnesium sulphate), concentrated and the residue subsequently distilled repeatedly with toluene. Yield: 64.0 g (quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH2:37][CH:38]3[CH2:40][CH2:39]3)[S:33]([CH3:36])(=[O:35])=[O:34])[CH2:22][CH2:21]2)=[O:19])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH2:37][CH:38]3[CH2:40][CH2:39]3)[S:33]([CH3:36])(=[O:35])=[O:34])[CH2:24][CH2:25]2)=[O:19])[CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](CC(=O)O)Cc2ccc(Cl)cc2)CC1

Procedure:
A solution of tert-butyl (3S)-3-[(4-chlorophenyl)-methyl]-4-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)-amino]phenyl}piperazinyl)-4-oxobutanoate (Step 5) (0.16 g, 0.27 mmol) in 10 mL of 50% TFA in CH2Cl2 mixture was stirred at RT for 2 h. The volatile solvent was removed in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo. (3S)-3-[(4-Chlorophenyl)-methyl]-4-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)-amino]phenyl}piperazinyl)-4-oxobutanoic acid was obtained as a light yellow solid (0.14 g) MS (ESI, pos. ion) m/z: 534.4 (M+1). Calc'd for C26H32ClN3O5S: 533.18. Anal. Calc'd for C26H32ClN3O5S.1.5H2O: C, 55.66; H, 6.29; N, 7.49; Cl, 6.32. Found: C, 55.51; H, 5.85; N, 7.35; Cl, 6.12.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:42]2[C:38](=[O:48])[C:39]3[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:41]2=[O:43])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
136 g (<528 mmol) 4-[1-tert-butoxycarbonylpiperidin-4-yl)-butan-1-ol (crude product), 135.3 g (516 mmol) Triphenylphosphine and 75.9 g (516 mmol) phthalimide are suspended in 1800 ml THF and 89.9 g (516 mmol) azodicarboxylic acid diethyl ester are added dropwise within three hours under protective atmosphere and light cooling (to ca. 15° C.). The mixture is left to stand at RT overnight without further cooling. Subsequently, the solvent is removed under vacuum and the oily residue is dissolved in 500 ml acetic acid ethyl ester and held at 0° C. overnight. The sedimented precipitate is filtered and discarded. The solution is concentrated under vacuum and the oily residue is chromatographically purified over silica gel with CHCl3 and crystallized from 200 ml isopropanol after drawing off the solvent. Colorless crystals remain with a MP of 100–102° C.; yield: 108.5 g (57%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=[C:7]([Br:17])[CH:6]=2.Cl.N1C=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OC)(OC)(OC)CCC>C1(C)C=CC=CC=1>[Br:17][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:20]([CH2:21][CH2:22][CH3:23])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: c1ccncc1
Reactant: Nc1cnc2cc(Br)ccc2c1NCCCO
Agent: CCCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 230.6 %

Procedure:
A mixture of 3-[(3-amino-7-bromoquinolin-4-yl)amino]propan-1-ol (7.2 g, 24 mmol), pyridine hydrochloride (1.05 g, 9.09 mmol) and trimethyl orthobutyrate (4.05 mL, 25.5 mmol) in toluene (240 mL) was heated at reflux for two hours under an atmosphere of nitrogen. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (100 mL). Aqueous sodium hydroxide (15 mL of 6 M) was added to the solution, and the resulting mixture was stirred for two hours at ambient temperature. A portion of the solvent was removed under reduced pressure, and the resulting mixture was adjusted to pH 7 with the addition of 6 N hydrochloric acid. The mixture was then extracted with chloroform (4>150 mL), and the combined extracts were washed sequentially with saturated aqueous sodium bicarbonate (40 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. An analysis by nuclear magnetic resonance spectroscopy indicated the presence of starting material, and the procedure was repeated using 1 mL trimethyl orthobutyrate and heating at reflux for one hour. Following the work-up procedure, the resulting solid was triturated with ethyl acetate and isolated by filtration to provide 7.30 g of 3-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[O-:24][C:25]#[N:26].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:25]([NH2:26])=[O:24])[CH2:14][CH:13]2[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#C[O-]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNCC1CN1CCCC1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C(CN2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A solution of 1-[(3,4-dichlorophenyl)acetyl]-2-(1-pyrrolidinylmethyl) piperazine (200 mg) in acetic acid (0.5 ml) and water (1 ml) was treated with a solution of sodium cyanate (73 mg) in water (0.5 ml). The resulting solution was stirred at room temperature for 2 h. The solvent was removed in vacuo, the residue was basified with aqueous 2N sodium carbonate solution and extracted with dichloromethane (2×25 ml). The combined organic extracts were dried and evaporated to give a foam (206 mg) which was purified by flash column chromatography eluting with dichloromethane:methanol:0.880 NH3 (200:8:1) to give a solid (120 mg). Crystallisation from ethyl acetate/methanol gave the title compound as a solid (58 mg) m.p. 206°-209° C.