Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]3([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=4)[CH2:24][O:23]C(C)(C)[O:21][CH2:20]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.O1CCOCC1.Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.CO>[F:1][C:2]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=3)([CH2:24][OH:23])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C2(NC(=O)c3c(C)nc4c(OCc5c(F)cccc5F)cccn34)COC(C)(C)OC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc(C(CO)(CO)NC(=O)c2c(C)nc3c(OCc4c(F)cccc4F)cccn23)c1
Reaction time: 14 h
Yield: 61.9 %

Procedure:
To 301 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[2,2-dimethyl-5-(3-methylphenyl)-1,3-dioxan-5-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide were added 3 ml of dioxane, 3 ml of methanol, and 6 ml of 1 M hydrochloric acid, followed by stirring for 14 hours. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution, water, and ethyl acetate under ice-cooling to carry out a layer separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography. To the obtained purified product were added hexane and ethyl acetate, and the insoluble material was collected by filtration and dried to obtain 172 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[1,3-dihydroxy-2-(3-methylphenyl)propan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([C:13]2[C:14]([C:19]([F:22])([F:21])[F:20])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:4][C:3]=1[O:23]C.[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1.Cl>ClCCCl>[OH:23][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[C:14]([C:19]([F:22])([F:20])[F:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: COc1cc(C(=O)c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(c1cc(O)c(O)c([N+](=O)[O-])c1)c1cccnc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (4-hydroxy-3-methoxy-5-nitrophenyl)(2-(trifluoromethyl)pyridin-3-yl)methanone (0.287 g, 0.84 mmol) in 1,2-dichloroethane (10 mL) cooled in an ice-water bath was added aluminium chloride (0.14 g, 1.05 mmol) in one portion followed by pyridine (0.26 g, 3.35 mmol) dropwise. The resulting red suspension was stirred at 80° C. for two hours, then cooled to room temperature and poured onto cold 2 N aqueous hydrochloric acid (100 mL). The precipitate was filtered off, washed with water and dried to give (3,4-dihydroxy-5-nitrophenyl)(2-(trifluoromethyl)pyridin-3-yl)methanone, 0.182 g, (66%).
Reaction SMILES: [C:1]1([CH:7]2[O:14][CH2:13][C@H:12]3[C@:10]([C:15](OCC)=[O:16])([CH2:11]3)[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([CH:7]2[O:14][CH2:13][C@H:12]3[C@:10]([CH2:15][OH:16])([CH2:11]3)[CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@@]12COC(c3ccccc3)OC[C@@H]1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@@]12COC(c3ccccc3)OC[C@@H]1C2
Temperature: 12.5 °C
Yield: 82.3 %

Procedure:
In a reactor, tetrahydrofuran (110.0 L) was charged under nitrogen, followed by addition of ethyl (1R,7R)-4-phenyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylate (11.0 kg, 41.9 mol). The mixture was stirred to get a clear solution and cooled to 10-15° C. Lithium aluminium hydride (2 M in tetrahydrofuran, 17.1 L, 35.6 mol) was added drop wise over a period of 1 hour by maintaining the temperature at 10-15° C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 0-5° C. and quenched with subsequent addition of ethyl acetate (55.0 L) and brine (55.0 L) maintaining that temperature. The temperature of the reaction mass was gradually raised to 20-25° C. and stirred for 1 h. The organic layer was separated and washed with water (55.0 L) and brine (55.0 L). The organic layer was dried over sodium sulfate (6.0 kg) and the solvent was distilled off. Petroleum ether (22.0 L) was added to the residue to precipitate the product and the slurry was cooled to 0-5° C. and stirred for 30 min. The slurry was filtered and washed with cold petroleum ether (5.0 L). The product was dried in a vacuum tray dryer for 4 hours below 40-45° C. to afford 7.6 Kg of the title compound (5c) as crude product.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@:6]21[C:32]1[C:27](=[CH:28][C:29]([Cl:42])=[C:30]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:40][CH3:41])=[CH:36][CH:35]=3)[CH:31]=1)[O:26][CH2:25][CH2:24]2)(=O)C.O(C)[Li]>CO>[Cl:42][C:29]1[CH:28]=[C:27]2[O:26][CH2:25][CH2:24][C@@:6]3([C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([CH2:19][OH:20])[O:7]3)[C:32]2=[CH:31][C:30]=1[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH3:41])=[CH:38][CH:39]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OCC[C@]32O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: [Li]OC
Solvent: CO
Product: CCc1ccc(Cc2cc3c(cc2Cl)OCC[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reaction time: 24 h

Procedure:
(2′S,3′R,4′S,5′R,6′R)-6′-(Acetoxymethyl)-7-chloro-6-(4-ethylbenzyl)-3′,4′,5′,6′-tetrahydrospiro[chroman-4,2′-pyran]-3′,4′,5′-triyl triacetate (19) (9.6 mg, 0.02 mmol) was dissolved in MeOH (0.2 mL) and treated with LiOMe (20 μL of a 1M solution in MeOH). After 24 h, the reaction mixture was filtered through a syringe filter and concentrated, then passed through a small SiO2 column, eluting with 5% MeOH/CH2Cl2 to provide a film (5.8 mg, 83%). 1H NMR (300 MHz, CD3OD) δ ppm: 7.37 (s, 1H), 7.05 (s, 4H), 6.79 (s, 1H), 4.33 (m, 1H), 4.13 (m, 1H), 3.97 (s, 2H), 3.78 (m, 2H), 3.48-3.62 (m, 3H), 3.33 (m, 2H), 2.57 (q, J=15, 7.8 Hz, 2H), 2.33-2.42 (m, 1H), 2.13-2.21 (m, 1H), 1.19 (t, J=7.5 Hz, 3H). LC/MS 100% (ELSD) tR=1.99 min, calcd for C23H27ClO6: 434.15, found 434.15 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: O=C(O)C1CNC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CC(C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and azetidine-3-carboxylic acid following General Procedure C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:42]=[CH:43][N:44]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCCC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCCC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-butylimidazol-2-yl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (108 mg) in dichloromethane (10 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-butylimidazol-2-yl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (140 mg) (Compound 346) as yellow amorphous.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[N:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[O:7])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccncc2)cc1

Procedure:
Using the procedure outlined in Example 58, the title compound was prepared from 4-bromo-N-quinolin-7-ylbenzamide (Example 82) (50 mg, 0.15 mmol) and 4-pyridylboronic acid (20 mg, 0.16 mmol) as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.86 (d, 1H), 8.70 (d, 2H), 8.33 (dd, 1H), 8.18 (d, 1H), 8.12 (d, 2H), 8.07 (s, 1H), 7.88 (d, 1H), 7.79 (d, 2H), 7.58(d, 2H), 7.38 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][OH:6].[F:9][C:10]1[C:15]([S:16](Cl)(=[O:18])=[O:17])=[C:14]([F:20])[C:13]([F:21])=[C:12]([F:22])[C:11]=1[F:23].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:9][C:10]1[C:11]([F:23])=[C:12]([F:22])[C:13]([F:21])=[C:14]([F:20])[C:15]=1[S:16]([O:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:8])[CH3:7])(=[O:18])=[O:17]
Reactant: COC(C)(C)CCO
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(C)(C)CCOS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 163 %

Procedure:
To a solution of 3-methoxy-3-methylbutane-1-ol (1.07 g, 9 mmol) and TEA (0.61 g, 6 mmol) in CH2Cl2 (12 mL) was added pentafluorobenzenesulfonyl chloride (0.99 g, 3.7 mmol). The solution was stirred at rt for 2 h. Saturated aqueous NaHCO3 (12 mL) was added to the solution and the mixture was stirred at rt for 30 min. The organics were extracted with CH2Cl2 (75 mL) and washed with 1 M HCl (2×25 mL), saturated aqueous NaHCO3 (1×25 mL) and saturated aqueous NaCl (1×25 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product (2.1 g, 81%). 1H NMR (400 MHz CDCl3) δ 4.42 (t, 2H, J=7.3 Hz), 3.13 (s, 3H), 1.97 (t, 2H, J=7.4 Hz), 1.17 (s, 6H); 19F NMR (400 MHz CDCl3) δ −137.9 (m, 2H), −146.65 (m, 1H), −161.01 (m, 2H). Anal. Calcd. For C12H13F5O4S: C, 41.38; H, 3.76. Found: C, 41.37; H, 3.77.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17]C)=[O:16])[OH:11])[CH3:3].[OH-].[Na+]>CO>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=[O:16])[OH:11])[CH3:1]
Reactant: COC(=O)c1cccc(C2(O)CCCCC2CN(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CC1CCCCC1(O)c1cccc(C(=O)O)c1
Yield: 92.2 %

Procedure:
A sample of methyl 3-[(1-RS,2-RS)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-benzoate (2.5 g, 8.6 mmol), MeOH (20 mL), and 3N NaOH (9 mL) were refluxed for 1.5 h. The MeOH was evaporated in vacuo and the residue was made acidic with HCl (conc). The solvent was evaporated in vacuo and the residue triturated with Et2O. The solid was dried overnight in vacuo to give 2.2 g (92%) 3-[(1-RS,2-RS)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-benzoic acid.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].Br[CH2:30][CH:31]=[CH2:32].[Cl-].[NH4+]>O1CCCC1.O>[CH2:32]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:2]1)[CH:31]=[CH2:30]
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
1-(1,1-Dimethylethyl) 3-ethyl 1,3-piperidinedicarboxylate (12.85 g, 50 mmol) in tetrahydrofuran (50 mL) was added slowly to a stirred, cooled (−78° C.) solution of potassium hexamethyldisilazide (14.96 g, 75 mmol) in tetrahydrofuran (75 mL). The mixture was stirred at −78° C. for 30 minutes, then 3-bromo-1-propene (6.49 mL, 9.07 g, 75 mmol) was added dropwise over 5 minutes. The mixture was stirred at −78° C. for 1 hour, then saturated aqueous ammonium chloride (200 mL) and water (100 mL) were added. The mixture was allowed to warm to room temperature and extracted with ethyl acetate (3×200 mL). The combined organic fractions were washed with aqueous citric acid (10%, 3×200 mL), saturated aqueous sodium hydrogen carbonate (200 mL) and brine (200 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give to give the title compound as a pale yellow oil (13.46 g, 91%). m/z (ES+) 298 (M+1).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][N:11]2CC=C)=[CH:6][CH:5]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>O.[Ru](Cl)(Cl)Cl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[NH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH2:15]2)=[CH:8][CH:9]=1
Reactant: C=CCN1CCN(C)C[C@H]1c1ccc(Cl)cc1
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCN[C@H](c2ccc(Cl)cc2)C1
Temperature: 100 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
In distilled water (9 mL), (R)-2-(4-Chlorophenyl)-4-methyl-1-(2-propenyl)hexahydropyrazine dihydrochloride (1.06 g, 3.0 mmol) produced in Example 20 was dissolved. To the solution, ruthenium chloride (28 mg, 0.04 equivalent) was added. The mixture was stirred at 100° C. for 12 hours. After toluene (9 mL) was added thereto, formed insolubles were removed by filtration, and washed with toluene (9 mL) and distilled water (9 mL). To the filtrate, 30 wt % aqueous solution of sodium hydroxide (918 mg, 2.5 equivalents) was added. After the organic layer and aqueous layer were separated, the organic layer was washed twice with distilled water (9 mL), concentrated and dried under vacuum, to obtain 448 mg of the title compound as pale brown oil (yield: 65%, chemical purity: 88.4 area %). The retention time in the chemical purity analysis method was 2.2 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:4][CH:3]1[C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=O)=[CH:13][CH:12]=1.N.C1([Mg]Br)C=CC=CC=1.CC1CC(CCC)CCC1=O.C(Cl)(=O)C.O=P(Cl)(Cl)Cl>CN(C=O)C.O>[CH3:1][CH:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:4][CH:3]1[C:11]1[CH:19]=[CH:18][C:14]([C:15]#[N:17])=[CH:13][CH:12]=1
Reactant: CCCC1CCC(c2ccc(C(N)=O)cc2)C(C)C1
Agent: Br[Mg]c1ccccc1
Agent: CCCC1CCC(=O)C(C)C1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCC1CCC(c2ccc(C#N)cc2)C(C)C1
Reaction time: 1 h

Procedure:
A solution of 22 g of p-(2-methyl-4-n-propylcyclohexyl)benzamide [obtainable from the acid chloride with NH3 ; the corresponding acid being obtainable by reacting phenylmagnesium bromide with 2-methyl-4-n-propylcyclohexanone (Example 1), elimination of water, hydrogenation of the resulting double bond, Friedel-Crafts acylation with acetyl chloride and subsequent haloform reaction] in 500 ml of DMF has added to it dropwise with stirring at 50° 65 g of POCl3. After further stirring for one hour the batch is poured onto ice and is worked up as customary to give p-(2-methyl-4-n-propylcyclohexyl)-benzonitrile.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[CH:3]1.[Br:12]Br.N>CC(O)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[C:10]([Br:12])[C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2cc(N)ccc21
Reactant: BrBr
Agent: N
Solvent: CC(=O)O
Product: Cn1cnc2c(Br)c(N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 1-methyl-5-aminobenzimidazole (0.36 g, 2.4 mmol) in 10 ml of AcOH was added Br2 (0.12 ml). The reaction mixture was stirred for 1 h at 25° C. and concentrated in vacuo, yielding an oil which was subjected to column chromatography (NH3 sat'd 3% MeOH/CHCl,) to yield 0.27 g (1.2 mmol, 50%) of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14]C(N3CCCCC3)[CH2:12][CH2:11]2)=[CH:6][N:5]=1)([O-:3])=[O:2].[CH:22]([N:25]1CCN(C2C=CC(N)=NC=2)CC1)([CH3:24])[CH3:23].CN1CCN(C2C=CC(N)=NC=2)CC1>>[CH:22]([N:25]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1ccc(N2CCC(N3CCCCC3)CC2)cn1
Reactant: CC(C)N1CCN(c2ccc(N)nc2)CC1
Agent: CN1CCN(c2ccc(N)nc2)CC1
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1

Procedure:
1-isopropyl-4-(6-nitro-3-pyridyl)piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted to 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine. 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.06 (d, J=6.44 Hz, 6H) 2.59-2.75 (m, 5H) 2.97-3.10 (m, 4H) 4.13 (s, 2H) 6.45 (d, J=8.78 Hz, 1H) 7.15 (dd, J=9.08, 2.93 Hz, 1H) 7.76 (d, J=2.93 Hz, 1H). LCMS (ESI) 221 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Cl.N>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)c1cccc(Cl)c1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(CN)c1cccc(Cl)c1
Temperature: 0 °C
Yield: 42.7 %

Procedure:
To a solution of 2-(3-chloro-phenyl)-2-methyl-propionitrile (6.4 g, 35.7 mmol) in THF (80 mL) was added borane-tetrahydrofuran complex solution (71.3 mL, 71.3 mmol), and the resulting mixture was heated to reflux for 5 hours. After cooling to 0° C., aq. HCl (2 M, 10 mL) was added dropwise to quench the reaction. The mixture was then concentrated in vacuo to afford a solid residue, which was treated with aq. ammonia solution (6M in H2O). After extraction with ethyl acetate, the organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 180 g, 5% methanol in dichloromethane) to yield the title compound as oil (2.8 g, 43%). MS: 184.1 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18]>>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:15](=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Reactant: CCCC(=O)Cl
Product: CCCC(=O)NC1C(=O)Nc2ccccc2NC1=O
Yield: 76.2 %

Procedure:
Using the method of Example 53, using 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (4.0 g, 20.9 mmol), butyryl chloride (2.45 g, 23.0 mmol) and overnight at RT gives the title compound (4.16 g, yield 76%); 1H NMR (300 MHz, DMSO-d6): δ 10.70 (s, 2H), 8.21 (d, 1H, J=7.8 Hz), 7.24-7.15 (m, 4H), 4.74 (d, 1H, J=7.5 Hz), 2.24 (t, 2H, J=7.2 Hz), 1.51-1.43 (m, 2H), 0.83 (t, 3H, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.C([NH:15][C:16]1[C:21]([C:22](OCC)=[O:23])=[CH:20][N:19]=[CH:18][N:17]=1)(=O)C>C(Cl)Cl>[NH2:15][C:16]1[C:21]([C:22]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:23])=[CH:20][N:19]=[CH:18][N:17]=1
Reactant: CCOC(=O)c1cncnc1NC(C)=O
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Nc1ncncc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
To a solution of aniline (336.0 mg, 3.6 mmol) in 7.5 mL of dry CH2Cl2 was slowly added 2.17 mL of Me3Al (2M solution in hexanes) at RT under N2. After 20 min of stirring compound 22 (301 mg, 1.44 mmol) was added to the reaction mixture as a solution in 2 mL of dry CH2Cl2. The reaction mixture was stirred at RT for 16 h and then quenched with NH4Cl (sat.) followed by extraction into CH2Cl2. The combined organic layers were washed with NaHCO3 (sat.), brine and dried over Na2SO4. The crude material was purified by flash chromatography (CH2Cl2/EtOAc) to yield 75.0 mg of the target compound 23 in 24% yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(#N)C>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1ccc(C=O)cc1
Yield: 848.3 %

Procedure:
4-Hydroxybenzaldehyde (1.00 g, 0.82 mmol), potassium carbonate (1.70 g, 12.28 mmol) and 1-iodooctane (2.16 g, 9.00 mmol) were heated together in acetonitrile at 80° C. for 16 h. The reaction was cooled, filtered and concentrated. Silica gel chromatography eluting with hexane/ethyl acetate (20:1) gave a colorless oil (1.63 g): 1H NMR (500 MHz) δ 9.99 (s, 1H), 7.44-7.46 (m, 2H), 7.40 (s, 1H), 7.19 (m, 1H), 4.01 (t, J=6.6 Hz, 2H), 1.80 (m, 2H), 1.42-1.50 (m, 2H), 1.24-1.39 (m, 8H), 0.89 (t, J=6.9 Hz, 3H).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:30][CH3:31])=O)C1C=CC=CC=1.CO>[C].[Pd].C(OCC)(=O)C>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:30][CH3:31]
Reactant: COC(=O)c1cc(OC)cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(OC)cc(N2CC[C@H](N)[C@H](OC)C2)c1

Procedure:
The same operation as in Example (40e) was performed using methyl cis(±)-3-(4-{[benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-methoxybenzoate obtained in Example (257b) (106 mg, 0.25 mmol), a 10% palladium-carbon catalyst (42 mg), methanol (2 mL) and ethyl acetate (2 mL), to obtain the title compound. The resulting compound was used for the next reaction without purification.