Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=CC=CC=3)=[CH:14][CH:13]=2)[C:7]([CH:26]=[CH:27][CH2:28][CH2:29][CH3:30])=[C:6]([CH:31]([CH3:33])[CH3:32])[N:5]=1)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[C:7]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:6]([CH:31]([CH3:32])[CH3:33])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(O)cc1
Reaction time: 14 h
Yield: 92.4 %

Procedure:
2,6-Diisopropyl-3-hydroxymethyl-4-(4benzyloxyphenyl)-5-(pent-1-enyl)pyridine (Example 160) (500 mg, 1.13 mmol) was dissolved in absolute ethanol (10 mL) under argon, treated with 10% palladium on carbon (15 mg), then stirred under a hydrogen atmosphere for 14 h. After purging the system with argon, the catalyst was removed by filtration through a pad of Celite. The solvent was removed and the residue purified by flash chromatography (5% methanol-methylene chloride) to yield 371 mg of the title compound as a waxy solid (mp 158.5° C.). 1H NMR (300 MHz, CDCl3): δ 0.79 (t, J=6.6 Hz, 3 H), 1.06-1.36 (m, 21 H), 2.24-2.31 (m, 2 H), 3.22 (sept, J=6.6 Hz, 1 H), 3.40 (sept, J=6.6 Hz, 1 H), 4.36 (d, J=5.4 Hz, 2 H), 4.85 (s, 1 H), 6.89 (d, J=8.4 Hz, 1 H), 7.05 (d, J=8.7 Hz, 1 H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:44](O)=O.C=O>ClC(Cl)C.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:44])[C:9]1([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CCC1(NCc2ccccc2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: O=CO
Agent: C=O
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CN(Cc1ccccc1)C1(CCC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 50 °C
Yield: 58.9 %

Procedure:
To a solution of the product of Example 74G (10 mg, 0.016 mmol) in dichloroethane (0.1 mL) was added formic acid (1.2 μL, 0.032 mmol) followed by addition of aqueous 37% formaldehyde solution (1.3 μL, 0.018 mmol). The mixture was heated at 50° C. for 2 h. After cooling to room temperature, the solution was diluted with ethyl acetate (1 mL), washed with water (0.5 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (2% methanol/dichloromethane) afforded a greenish brown solid (6 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.31-0.50 (m, 1H), 0.73 (s, 9H), 0.90-1.07 (m, 1H), 2.11-2.30 (m, 1H), 2.35-2.48 (m, 1H), 2.71 (s, 3H), 3.00-3.10 (m, 3H), 3.45-3.62 (m, 1H), 4.07 (d, J=12.87 Hz, 1H), 7.26-7.40 (m, 5H), 7.42-7.60 (m, 3H), 7.64 (t, J=7.54 Hz, 1H), 7.71-7.80 (m, 1H), 7.93 (d, J=8.09 Hz, 1H), 8.22 (d, J=6.62 Hz, 1H), 10.06 (s, 1H), 13.53 (s, 1H); MS m/z 637.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:15][CH:14]=[C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[NH:9][C:4]2=[C:3]1[C:16]#[N:17].C(O)(=O)C.[Br:22]Br>C(Cl)(Cl)(Cl)Cl>[Br:22][C:12]1[CH:11]=[CH:10][C:8]2[NH:9][C:4]3[C:5](=[CH:14][NH:15][C:2](=[O:1])[C:3]=3[C:16]#[N:17])[S:6][C:7]=2[CH:13]=1
Reactant: N#Cc1c2c(c[nH]c1=O)Sc1ccccc1N2
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1c2c(c[nH]c1=O)Sc1cc(Br)ccc1N2

Procedure:
To a solution of 20 parts of 2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile in 1575 parts of glacial acetic acid is added a solution of 34 parts of bromine in 320 parts of carbon tetrachloride. The resultant mixture is heated at the boiling point under reflux for 23/4 hours, then chilled. The precipitate which forms is filtered off and recrystallized from N,N-dimethylformamide to give 8-bromo-2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile melting above 305°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13]([CH3:20])=[CH:14][CH:15]=[N:16]3)=[CH:11][C:10]=2[C:21](O)=[O:22])=[C:4]([F:24])[CH:3]=1.[CH:25]1([CH2:28][O:29][NH2:30])[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][O:29][NH:30][C:21]([C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([F:19])[C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:24])[N:16]=[CH:15][CH:14]=[C:13]3[CH3:20])=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)O)cc12
Reactant: NOCC1CC1
Product: Cc1ccnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NOCC3CC3)cc12

Procedure:
The title compound is prepared from 7-(4-bromo-2-fluorophenylamino)-8-fluoro-4-methyl-quinoline-6-carboxylic acid in the same manner described in step J for Example 1 using O-cyclopropylmethyl-hydroxylamine in place of O-(2-vinyloxy-ethyl)-hydroxylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:10][CH3:14])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)cc(F)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1c(F)cc(Br)cc1C=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
928 mg of 5-bromo-3-fluoro-2-hydroxybenzaldehyde was dissolved in 3 ml of N,N-dimethylformamide, and 0.5 ml of methyl iodide and 1 g of potassium carbonate were successively added, followed by stirring for 1 hour at 50° C. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated, to give 926 mg of 5-bromo-3-fluoro-2-methoxybenzaldehyde. This crude product was dissolved in 4 ml of ethanol and 2 ml of tetrahydrofuran, and 200 mg of sodium tetrahydroborate was added, followed by stirring for 0.5 hours at room temperature. The reaction was quenched with 1 N-hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 3:1), to give 907 mg of 5-bromo-3-fluoro-2-methoxybenzyl alcohol.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:29]=[N:30][N:31]([CH2:33][C@H:34]5[O:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]5)[CH:32]=4)[N:22]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:29]=[N:30][N:31]([CH2:33][C@H:34]5[O:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]5)[CH:32]=4)[N:22]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(C(=O)c6ccccc6)cn5)CC4)n3)cn2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(C(O)c6ccccc6)cn5)CC4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl 2-((4-(4-(4-(5-benzoylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (80 mg, 0.127 mmol) in THF/methanol was added sodium borohydride (20 mg, 0.51 mmol). The mixture was stirred at room temperature for 1 hour, and LCMS showed the reaction was completed. The solvents were removed to give (S)-tert-butyl 2-((4-(4-(4-(5-(hydroxy(phenyl)methyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (80 mg, crude) as a yellowish solid. (MS (ES+) C31H39N11O4 requires: 629, found: 630 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][CH2:18][CH2:19][OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][CH2:18][CH:19]=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(CCCO)nc2ccccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(CCC=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of 3-(1-tert-butoxycarbonyl-Benzimidazol-2-yl)propan-1-ol (186 mg, 0.67 mmol) in CH2Cl2 (4 mL) was added Dess-Martin reagent (314 mg, 0.74 mmol) and the resulting mixture was allowed to stir at room temperature under N2 for 1 hour. The mixture was further diluted with 300-mL ethyl acetate, and washed with 1N NaOH, brine and dried over Na2SO4. Evaporation of the solvent and flash chromatograph of residue over silica gel, using 20% ethyl acetate in CH2Cl2, gave the title compound (141 mg, 76%) as pure white solid. 1H NMR (CDCl3) □ 1.72 (s, 9H), 3.13 (t, 2H, J=6.8 Hz), 3.52 (t, 2H, J=6.8 Hz), 7.28-7.34 (m, 2H), 7.66-7.67 (m, 1H), 7.87-7.91 (m, 1H), 9.97 (s, 1H).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][O:6][C@H:5]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=2[F:16])[C@@H:4]([N+:17]([O-])=O)[CH2:3]1.Cl.CCOCC.[OH-].[Na+]>C(O)C.[Zn]>[CH2:1]=[C:2]1[CH2:7][O:6][C@H:5]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=2[F:16])[C@@H:4]([NH2:17])[CH2:3]1
Reactant: C=C1CO[C@H](c2cc(F)c(F)cc2F)[C@@H]([N+](=O)[O-])C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: C=C1CO[C@H](c2cc(F)c(F)cc2F)[C@@H](N)C1
Reaction time: 1 h

Procedure:
To a vigorously stirred suspension of (2R,3S)-5-methylene-3-nitro-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran (200 mg, 0.73 mmol) and zinc powder (561 mg, 8.59 mmol) in ethanol (7 mL) was added 6N hydrochloric acid (2.3 mL, 14 mmol). After one hour, the mixture was treated with ether (100 mL) and aqueous sodium hydroxide solution (2.5N, 40 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to yield (2R,3S)-5-methylene-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)O.[OH-].[Na+]>Cl>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[CH:12][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCCNC1CCCCC1C(O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: OCCCNC1CCCCC1=Cc1ccccc1

Procedure:
A mixture of N-(3-hydroxypropyl)-N-[2-[phenyl(hydroxy)methyl]cyclohexyl]amine, from step (a) above, 50 g (0.19 mole) and 250 ml of concentrated hydrochloric acid was heated on a steam bath for 1.5 hr. The resulting solution was cooled in ice, basified with 20% aqueous sodium hydroxide solution and the product was extracted well with diethyl ether. The ether extract was dried with magnesium sulfate and evaporated to give 45.3 g of N-(3-hydroxypropyl)-N-[2-(phenylmethylene)cyclohexyl]amine, as an oil, which was used directly in the next preparative step. However, a portion of this amine oil was converted to its hydrochloride in methanol with a diethyl ether solution of hydrogen chloride and the salt was crystallized from the methanol/diethyl ether mixture, mp 175°-177° C. The IR, UV and NMR spectra were consistent.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([N:18]([CH2:27][CH2:28][CH2:29][CH3:30])[C:19]1[CH:26]=[CH:25][C:22](C=O)=[CH:21][CH:20]=1)CCC>N1CCCCC1>[CH2:4]([NH:1][C:19]1([NH:18][CH2:27][CH2:28][CH2:29][CH3:30])[CH:20]=[CH:21][C:22]([CH:11]=[CH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:25][CH2:26]1)[CH2:5][CH2:6][CH3:7]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Product: CCCCNC1(NCCCC)C=CC(C=Cc2ccc([N+](=O)[O-])cc2)=CC1
Yield: 43.6 %

Procedure:
The title compound was prepared from p-nitrophenylacetic acid (9.92 g, 0.055 mol) and 4-dibutylamino-benzaldehyde (14.32 g, 0.055 mol) in piperidine (5 mL) using the procedure described in Example 1, Step A. This procedure yielded a red solid, 4.12 g (0.012 mol, 16%) of the desired product.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH:13]1([CH2:19][CH:20]([NH:24][C:25](=[N:27][S:28]([CH3:31])(=[O:30])=[O:29])C)[C:21]([OH:23])=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[NH2:32][C@@H:33]([CH2:45][CH3:46])[CH:34]([C:36]1[O:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1)[OH:35].CN1CCOCC1>C(Cl)Cl.Cl>[O:37]1[C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=[C:36]1[CH:34]([OH:35])[C@@H:33]([NH:32][C:21](=[O:23])[CH:20]([NH:24][CH:25]=[N:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:19][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:45][CH3:46]
Reactant: CC(=NS(C)(=O)=O)NC(CC1CCCCC1)C(=O)O
Reactant: CC[C@H](N)C(O)c1nc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)C(CC1CCCCC1)NC=NS(C)(=O)=O)C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 91.1 %

Procedure:
A mixture of ethyldimethylaminopropyl carbodiimide hydrochloride (0.198 g, 1.14 mmol), hydroybenzotriazole (0.114 g, 0.742 mmol), 3-cyclohexyl-2-(1-methanesulfonyliminoethylamino)-propionic acid (0.205 g, 0.742 mmol) and 2(S)-amino-1-benzoxazol-2-ylbutan-1-ol (0.153 g, 0.743 mmol) in methylene chloride (6 mL) was cooled in an ice bath and then N-methylmorpholine (0.155 g, 1.55 mmol) was added to the reaction mixture which was then stirred at room temperature for 40 min. The reaction mixture was diluted with ice water and dilute hydrochloric acid and the product extracted with ethyl acetate. The extracts were washed with aqueous sodium bicarbonate, then brine, then dried over magnesium sulfate and evaporated to give of N-[1(S)-(benzoxazol-2-ylhydroxymethyl)propyl]-3-cyclohexyl-2-[(methanesulfonyliminomethyl)-amino]propionamide (0.314 g). Exact mass 464.21. Found: M+H=465.3, M+Na=487.3, M−H=463.1.
Reaction SMILES: Cl.C1(C(C2C=CC=CC=2)CC2CCNCC2)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[CH:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1>CCCCCC>[F:43][C:40]1[CH:41]=[CH:42][C:37]([CH:29]([C:26]2[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=2)[CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:38][CH:39]=1
Reactant: Fc1ccc(C(=CC2CCNCC2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: c1ccc(C(CC2CCNCC2)c2ccccc2)cc1
Solvent: CCCCCC
Product: Fc1ccc(C(CC2CCNCC2)c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared in the same manner as 4-(2,2-diphenylethyl)piperidine HCl starting from 4-[2,2-bis(4-fluorophenyl)ethenyl]piperidine, 0.15 molar hexane solvate. The resulting clear, colorless, oil was used directly in the next steps.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Na].Cl[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][C@H:31]([CH3:35])[CH2:30]3)=[CH:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1>ClCCl>[N:5]1([CH2:4][CH2:3][CH2:2][O:1][C:15]2[CH:16]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][C@H:31]([CH3:35])[CH2:30]4)=[CH:23][CH:24]=3)[CH:18]=[CH:13][N:14]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C[C@H]1CCCN(CCCOc2ccc(-c3ccnc(Cl)c3)cc2)C1
Reactant: OCCCN1CCCCC1
Agent: [Na]
Solvent: ClCCl
Product: C[C@H]1CCCN(CCCOc2ccc(-c3ccnc(OCCCN4CCCCC4)c3)cc2)C1
Temperature: 25 °C
Yield: 15.5 %

Procedure:
To 1-(3-hydroxypropyl)piperidine (287 mg) are successively added sodium (46 mg) and 2-chloro-4-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyridine (345 mg). The mixture is heated overnight, cooled back to room temperature and dissolved in dichloromethane (20 mL). The organic phase is washed with water (20 mL), dried over magnesium sulphate, concentrated under reduced pressure and purified over silica gel (eluent (dichloromethane/methanol from 100/0 to 90/10). Fraction containing the expected product are pooled and concentrated under reduced pressure. The crude base is dissolved in ethanol, oxalic acid (32 mg) is added and the precipitate that appears separated by filtration and dried to give 70 mg of 2-(3-piperidinopropoxy)-4-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyridine, dioxalate as a white solid melting at 122° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([NH2:11])[N:3]=1.O.[C:13]1([C:19]([CH:21]=O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.[Ni]>[C:13]1([C:19]2[N:1]=[C:2]3[N:3]=[C:4]([NH2:11])[CH:5]=[CH:6][C:7]3=[N:8][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc([N+](=O)[O-])c(N)n1
Reactant: O=CC(=O)c1ccccc1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Nc1ccc2ncc(-c3ccccc3)nc2n1

Procedure:
A solution of 1.22 g of 2,6-diamino-3-nitropyridine (7.92 mmol) in 210 ml of ethanol is hydrogenated with Raney nickel as catalyst at 50° C. and 5 bar. After the hydrogenation is complete, the catalyst is filtered off with suction through a glass fibre filter. Before the filtration, 1.68 g of phenylglyoxal hydrate (11.03 mmol) are introduced into 50 ml of ethanol in the receiver. The catalyst is then filtered off under nitrogen as protective gas, and the hydrogenation solution is sucked directly into the reaction flask. The greenish blue reaction mixture is heated under reflux under nitrogen for 30 min. The mixture is allowed to cool, and the solvent is removed in vacuo. A dark brown solid is finally obtained. Purification by column chromatography on silica gel (mobile phase dichloromethane/methanol mixture) affords a pale yellow crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cn1ccc2ccc(N)cc21
Temperature: 70 °C
Yield: 40.2 %

Procedure:
1-methyl-6-nitro-1H-indole (90 mg, 0.51 mmol), ammonium chloride (55 mg, 1.02 mmol) and iron powder (143 mg, 2.55 mmol) were suspended in ethanol/water (2 mL/1 mL) and heated at 70° C. for 2 h. After cooling, the solution was filtrated through a pad of Celite®, which was washed with ethanol. Ethyl acetate was added to the filtrate and the organic layer was washed with water twice. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 30 mg (37%) of the title compound
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[C:26]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: O=C1CCCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCN(C3CCCCCC3)CC2)nc1
Temperature: 50 °C
Reaction time: 96 h
Yield: 72.1 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with excess cycloheptanone (1.48 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 96 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol provided 0.41 g (72%) of the title compound as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[S:3]1.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([C:13](=[O:15])[C:12]([NH:11][C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[S:3][C:4]=3[CH:10]=2)=[O:16])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)sc2c1
Solvent: CCOCC
Product: O=C(Nc1ccc2[nH]c(=O)sc2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-benzothiazole-6-yl)-oxalamic acid and 4-benzylpiperidine according to the method described in Example 1c. Melting Point: 201-203° C. (diethylether)
Reaction SMILES: [OH2:1].Cl[C:3]1[N:4]=[N:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:8]=1.[OH-].[Na+]>C(O)=O>[O:9]([C:6]1[CH:7]=[CH:8][C:3](=[O:1])[NH:4][N:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O
Reactant: Clc1ccc(Oc2ccccc2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: O=c1ccc(Oc2ccccc2)n[nH]1
Temperature: 95 °C

Procedure:
3.1 21 ml of water are added to a solution of 3.10 g (15.0 mmol) of 3-chloro-6-phenoxypyridazine in 21 ml of formic acid, and the mixture is heated at 95° C. for 85 hours. The reaction mixture is cooled and brought to a pH of 6 using 23% aqueous sodium hydroxide solution. The precipitate formed is filtered off with suction, washed with water and dried in vacuo, giving 6-phenoxy-2H-pyridazin-3-one as colourless crystals; ESI 189.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]2[CH2:9][NH:8][CH2:11]2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(OC2CNC2)cc1

Procedure:
Palladium hydroxide (500 mg) and 1-(diphenylmethyl)-3-(4-fluorophenoxy)azetidine (500 mg, 1.50 mmol) were combined in ethanol (50 mL) and hydrogenated at 50 psi for 18 h. The reaction mixture was then filtered through Celite and concentrated in vacuo. The residue was purified via silica gel chromatography (Eluant: 00:5:2 chloroform:MeOH: concentrated aqueous ammonium hydroxide) to provide C40. Yield: 188 mg, 1.12 mmol, 75%. LCMS m/z 168.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.44 (br s, 1H), 3.76 (m, 2H), 3.89 (m, 2H), 4.91 (m, 1H), 6.66 (m, 2H), 6.93 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 4.55, 70.81, 115.43, 115.51, 115.76, 115.99, 152.96, 156.15, 158.53.