Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].Cl.[NH2:28]O.Cl>CO.CO.O.O>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:28][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](CCC(C)(C)C)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1CCC(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A solution of cis-methyl 2-(3,3-dimethylbutyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.78 g, 5.22 mmol) in MeOH (3.9 mL) was added to a solution of NaOH (288 mg, 7.2 mmol) in MeOH/H2O (4.4 mL/0.3 mL) at −30° C. After 10 min was added hydroxylamine hydrochloride (726 mg, 10.45 mmol) and NaOH (418 mg, 10.45 mmol) in MeOH (5.2 mL) and H2O (5.2 mL). Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (7.7 mL) at 80° C. and heated at 80° C. for 1 h. Concentration of the organic solvent and extraction with DCM (×2), drying using a phase separator and evaporation gave an orange oil. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 30-60% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,3-dimethylbutyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (717 mg, 44%) was isolated. 1H NMR (400 MHz, cdcl3) δ 0.79 (s, 9H), 1.01-1.19 (m, 2H), 1.23-1.48 (m, 2H), 1.83-1.96 (m, 2H), 1.98-2.11 (m, 2H), 2.94-3.04 (m, 1H), 3.09-3.19 (m, 1H), 3.70 (s, 3H), 3.91-4.06 (m, 2H), 5.71 (d, 1H). MS m/z 311 (M+H)+
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=2[NH:8][CH:7]=1>C(O)(=O)C.[Pd]>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[N:6]1[C:10]2[CH2:11][CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14][C:9]=2[NH:8][CH:7]=1
Reactant: COC(=O)c1ccc2nc[nH]c2c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)C1CCc2nc[nH]c2C1
Yield: 101 %

Procedure:
In 600 ml of acetic acid was dissolved 40.0 g of methyl 5-benzimidazole carboxylate sulfate in a 1 l-volume autoclave, and 11 g of 10% palladium-on-carbon was added to the solution as a catalyst to conduct hydrogenation at 80° C. at a pressure of 60 atm for 5 hours. The catalyst was separated by filtration, and the mother liquor was concentrated under reduced pressure to obtain 41.0 g of methyl 4,5,6,7-tetrahydrobenzimidazole-5-carboxylate sulfate as an oil. ##STR11##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Br:15]Br.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:15][CH:9]([C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C(Br)C(=O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of methyl 3-(4-fluorophenyl)-3-oxopropanoate 76 (1 equiv, 500 mg, 2.55 mmol) in DCM (17 mL) was added a solution of bromine (1.3 equiv, 530 mg, 3.31 mmol) in DCM (1.5 mL) in a drop wise manner at 0° C. The reaction mixture was stirred further for an additional 1 h and then treated with 10% aqueous K2CO3 (5 mL) solution. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 2-bromo-3-(4-fluorophenyl)-3-oxopropanoate 78 (700 mg, 100% yield). LRMS (ESI): (calc) 273.96 (found) 275.108 (MH+)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[C:11]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:12]=3)[C:7](=[O:34])[C:6]([C:35]([O:37]CC3C=CC(OC)=CC=3)=[O:36])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([O:24][CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)=[C:11]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[CH:12]=3)[C:7](=[O:34])[C:6]([C:35]([OH:37])=[O:36])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(COC(=O)c2cn(C3CC3)c3cc(OCc4ccc(OC)cc4)c(OCc4ccc(OC)cc4)cc3c2=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(COc2cc3c(=O)c(C(=O)O)cn(C4CC4)c3cc2OCc2ccc(OC)cc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a suspension of 4-methoxybenzyl 1-cyclopropyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (14 g, 22.52 mmol) in a mixture of Methanol (100 mL) and Water (50.0 mL) was added KOH (2.53 g, 45.0 mmol) portionwise. The resulting mixture was stirred at 90° C. for 2 h. LCMS indicated completion of the reaction. The reaction mixture was cooled down to r.t. and concentrated, and was then diluted with water and adjusted pH to 1 using 2 N HCl (aq.). The precipitates were collected by filtration and dried to afford 1-cyclopropyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (11 g, 21.93 mmol, 97% yield) as pale yellow solid. LCMS: [M+H]+: 502.3.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][CH2:8][CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(OC)(C)C>O.C(Cl)Cl>[CH2:12]([O:11][CH:10]([O:14][CH2:15][CH3:16])[CH2:9][CH2:8][NH:7][S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])[CH3:13]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(CCN)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(CCNS(=O)(=O)c1ccccc1)OCC
Temperature: 20 °C

Procedure:
To a suspension of sodium carbonate (31 g, 0.37 mol) in water (50 ml) was added a solution of 1-amino-3,3-diethoxypropane (10.00 mL, 61.81 mmol) in DCM (50 mL) followed by cooling to 0° C. benzenesulfonyl chloride (7.65 mL, 60.0 mmol) was added at 0° C. with vigorous stirring followed by warming to 20° C. and continued stirring for 2 h after which time MTBE (150 mL) was added. Organic layer was separated, washed with 1.0 M of HCl (50 mL), saturated NaHCO3 (50 g), water (50 g), concentrated and azeotroped to dry two times with MTBE (150 mL×2) to provide N-(3,3-diethoxypropyl)benzenesulfonamide, 28 (17.34 g, 60.34 mmol, 97% yield) as light yellow clear oil.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.ClC1C2C(C3C=CC(CC)=CC=3)=C(C3C=CC=CC=3)OC=2N=CN=1.[CH2:49]([OH:53])[C@@H:50]([OH:52])[CH3:51].C(O)[C@H](O)C>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([O:52][C@H:50]([CH3:51])[CH2:49][OH:53])=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: C[C@H](O)CO
Agent: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: C[C@@H](O)CO
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H](C)CO)c23)cc1

Procedure:
Production of the compounds listed in the following table is analogous to the synthesis described above. It starts correspondingly from 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]-pyrimidine or from 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine and uses (2S)-propane-1,2-diol or (2R)-propane-1,2-diol respectively:
Reaction SMILES: C(=O)=O.C(O)(C)C.[CH2:8]([C:15]1[O:16][C:17]2[CH:35]=[CH:34][CH:33]=[CH:32][C:18]=2[C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][C:23]=1[O:30]C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.B(Br)(Br)Br>C(Cl)Cl>[CH:32]1[C:18]2[C:19]3[C:20]([C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=4[OH:30])=[C:10]4[C:9](=[CH:8][C:15]=3[O:16][C:17]=2[CH:35]=[CH:34][CH:33]=1)[CH:14]=[CH:13][CH:12]=[CH:11]4
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)oc3ccccc23)c(OC)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)O
Product: Oc1ccc(-c2c3ccccc3cc3oc4ccccc4c23)c(O)c1
Temperature: 25 °C
Reaction time: 45 h
Yield: 38.4 %

Procedure:
To a cold (-76° C. dry ice, isopropanol bath) solution of (2-benzyl-benzofuran-3-yl)-(2,4-dimethoxy-phenyl)-methanone (6.13 g, 16.5 mmol) in anhydrous methylene chloride (60 mL) was added a 1 M solution of boron tribromide in methylene chloride (100 mL, 100 mmol, 6.06 eq) dropwise over a period of 20 minutes under a dry nitrogen atmosphere. The dry ice bath was removed and the reaction mixture was stirred at ambient temperature for 45 hours. After cooling in an ice bath water was carefully added and after quenching the reaction mixture was further diluted with water (300 mL). The organics were extracted with diethyl ether and methylene chloride. The extracts were combined, washed with water and brine, and combined with silica gel. The solvents were removed and the adsorbate was flash chromatographed (80/20 petroleum ether/ethyl acetate) to provide the title compound as a white solid (2.07 g, 38%): mp 201 -202° C.; NMR (CDCl3); δ8.03 (ddd, J=8, 7, 1 1 H), 8.01 (s, 1 H), 7.82 - 7.79 (m, 1 H), 7.58 - 7.54 (m, 2 H), 7.48 - 7.43 (m, 2 H), 7.20 (d, J=8 Hz, 1 H), 7.18 - 7.15 (m, 2 H), 6.70 (m, 2 H), 5.00 (s, 1 H), 4.70 (s, 1 H); Hi Res MS, Calc. Sample Mass for C22H14O3, 326.0942951, Measured Mass 326.09019, mas deviation 4 mmu. Anal. Calc. for C22H14O3: C, 80.97, H, 4.32, N, 0.00. Found: C, 79.80, H, 4.10, N, 0.07.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]([NH2:18])=O)[CH:11]=[CH:12][CH:13]=1>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][NH2:18])[CH:11]=[CH:12][CH:13]=1
Reactant: NC(=O)C=Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 1.0 M solution of LiAlH4 in THF (6.0 mL) was added dropwise to a suspension of 3-(3-chloro-phenyl)-acrylamide prepared of Preparation 12, Step A (1.0 g, 5.51 mmol) in 30 mL THF at 0° C. The reaction was warmed to room temperature and was stirred for 5 h. An additional 4 mL of 1 M LiAlH4 was added and the reaction was stirred for 18 h. An additional 2 mL of 1 M LiAlH4 was added and the reaction was stirred for 24 h. The reaction mixture was quenched by dropwise addition of water. The mixture was concentrated in vacuo to remove THF and was diluted with water. The aqueous solution was extracted with EtOAc. The organic solution was washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in CHCl3 and the organic solution was washed with 1M HCl. The aqueous solution was basified to pH 11 with 1M NaOH and the product was extracted into CHCl3. The organic solution was dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a yellow oil (0.134 g). 1H NMR (400 MHz, CDCl3) δ 7.20-7.22 (m, 3H), 7.16 (m, 1H), 2.74 (t, 2H), 2.61 (t, 2H), 1.74 (m, 2H); MS 170 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10](O)[C:9]2=[O:21])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:25])=O>CN(C=O)C>[Cl:25][C:10]1[C:9](=[O:21])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12](=[O:13])[C:11]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C(O)=C(c2ccccc2)C(=O)N1c1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
After dissolving compound 6d (1.00 g, 3.33 mmol) in MC (10 ml) and anhydrous DMF (10 ml), oxalyl chloride (0.850 g, 6.66 mmoL) was added thereto and the agitation for 30 minutes was carried out. After the identification of the reaction progress with TLC, the reaction was terminated. Then, three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4, solvents were removed and then, the column chromatography was carried out with EA/HX ( 1/15). The suspension was carried out with HX to obtain compound 7d.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[C:5]([N+:8]([O-])=O)=[N:6][CH:7]=1.Cl.N>C(O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1OCc1ncccc1F
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CCO
Product: Nc1ncc(Cl)cc1OCc1ncccc1F

Procedure:
Under argon, 29.8 g (105.1 mmol) of 5-chloro-3-[(3-fluoropyridin-2-yl)methoxy]-2-nitropyridine from Example 126A were initially charged in 317 ml of ethanol. 18.2 g (325.7 mmol) of iron powder were added, and the reaction mixture was heated to reflux. 80.4 ml of conc. hydrochloric acid were slowly added dropwise, and the mixture was heated under reflux for a further 6 h. The reaction mixture was made alkaline with 33% strength aqueous ammonia solution and then concentrated under reduced pressure. Purification by silica gel chromatography (mobile phase: dichloromethane/methanol gradient: 95/5 to 90/10) gave 25.0 g (94% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]([N:13]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:14]3[CH2:19][C@@H:18]([C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)=[O:12])[N:8]([CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:7]=2[CH:45]=1.C(OCC)(=O)C.[ClH:52]>>[ClH:52].[ClH:52].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]([N:13]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:14]3[CH2:19][C@@H:18]([C:20]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[O:21])[CH2:17][NH:16][CH2:15]3)=[O:12])[N:8]([CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:7]=2[CH:45]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccc(OC)cc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-{{{6-methoxy-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (82 mg) was dissolved in 2M hydrogen chloride-ethyl acetate (3 ml), and the mixture was stirred at room temperature for 1 hr and concentrated to give the object product (78 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].[H-].[Na+].Cl[CH2:13][C:14]1[N:18]=[C:17]([CH3:19])[O:16][N:15]=1>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:13][C:14]1[N:18]=[C:17]([CH3:19])[O:16][N:15]=1
Reactant: Cc1nc(CCl)no1
Reactant: Sc1cccc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(CSc2cccc(Cl)c2Cl)no1
Reaction time: 2 h
Yield: 40.7 %

Procedure:
7.0 g (39.1 mmol) of 2,3-dichloro-thiophenol are introduced into 50 ml of absolute tetrahydrofuran, the mixture is treated with 1.2 g (0.039 mmol) of 80% sodium hydride dispersion in portions and stirred for 2 hours at reflux temperature. The mixture is subsequently treated with 4.5 g (33.9 mmol) of 3-chloromethyl-5-methyl-1,2,4-oxadiazole at room temperature and stirred until the reaction is complete (approximately 10 to 15 hours). The sodium chloride which has precipitated is subsequently separated off and the entire batch is concentrated in vacuo. The crude product which remains can be chromatographed over a silica gel column (silica gel 60-Merck, particle size: 0.040 to 0.063 mm) using toluene as the eluent. 3.8 g (36.5% of theory) of 3-(2,3-dichlorophenylthiomethyl)-5-methyl-1,2,4-oxadiazole are obtained.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:24][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: OC1CCCCC1
Product: N=C(OC1CCCCC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and cyclohexanol there is obtained cyclohexyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, 1H-NMR(CDCl3): 1.5-2.1 (8H), 4.2 (s, 4H), 4.67 (broad s, NH), 5.1 (m, OCH), 7.3-7.7 (8H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([NH:12]C(=O)C)=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH-].[Na+]>Cl>[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ccc2c(c1)OCCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCOc2cc(N)ccc21
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of N-(4,4-dimethyl-chroman-7-yl)-acetamide (1.35 g, 6.2 mmol) in 20% HCl solution (30 mL) was heated at reflux for 3 h and then cooled to room temperature. The reaction mixture was basified with 10% aq. NaOH to pH 8 and extracted with EtOAc (30×3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to give 3,4-dihydro-4,4-dimethyl-2H-chromen-7-amine (C-5) (1 g, 92%). 1H NMR (DMSO-d6) δ 6.87 (d,J=8.4 Hz, 1 H), 6.07 (dd,J=8.4, 2.4 Hz, 1 H), 5.87 (d,J=2.4 Hz, 1 H), 4.75 (s, 2 H), 3.99 (t,J=5.4 Hz, 2 H), 1.64 (t,J=5.1 Hz, 2 H), 1.15 (s, 6 H); ESI-MS 178.1 m/z (MH+).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[NH:7][C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>O1CCCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:25](=[O:26])[C:24]2[CH:28]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=2[O:29][CH3:30])/[NH:7][C:6]=1[CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: Cc1[nH]c(=N)sc1C(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1/[nH]c(C)c(C(C)(C)C)s1
Temperature: 60 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
A mixture of 5-tert-butyl-4-methylthiazol-2(3H)-imine (250 mg, 1.5 mmol) in tetrahydrofuran (10 mL) was treated with triethylamine (0.25 mL, 1.8 mmol) and 5-chloro-2-methoxybenzoylchloride (307 mg, 1.5 mmol). The reaction mixture was stirred at 60° C. for 18 hours then concentrated under, reduced pressure. The residue was diluted with ethyl acetate and H2O. The organic extract was dried over MgSO4, filtered, concentrated under reduced pressure and dried under vacuum to afford the title compound (490 mg, 96% yield). MS (ESI) m/z 339 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13])[CH3:5].Cl>CO>[CH3:5][N:4]([CH:6]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[OH:13])[CH3:3]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)C(c1ccccc1)C1CCCCC1O
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A total of 28.3 g (747 mmole) sodium borohydride, dissolved in 650 ml methanol, were added in portions to 80.0 g (299 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 (2nd stage), and the mixture was subsequently stirred for one hour. For working up, 680 ml dilute hydrochloric acid (1 N) were added, and the mixture was extracted with 500 ml ether. The aqueous phase was rendered alkaline (pH≧10) with 25 vol. % ammonia solution and extracted three times with 250 ml ether each time. The combined organic extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator (500 to 10 mbar). 65.2 g (94% of theoretical) 2-(dimethylaminophenylmethyl)cyclohexanol were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[N:32]1[CH:37]=[CH:36][CH:35]=[N:34][C:33]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:41]4[CH2:42][CH2:43][N:38]([C:33]5[N:32]=[CH:37][CH:36]=[CH:35][N:34]=5)[CH2:39][CH2:40]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2ncccn2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(2-pyrimidinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=593.98 (M+H+); retention time=0.84 minutes.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[CH2:12]([C:14]([C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1)=[O:15])[CH3:13].O>C(O)C>[CH3:13][CH:12]1[CH:2]2[N:3]([CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]2[C:14]1=[O:15]
Reactant: CCC(=O)C1=CCCCC1
Reactant: C1=NCCc2ccccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1C(=O)C2CCCCC2N2CCc3ccccc3C12

Procedure:
A mixture of 16.75 g (0.1 mole) of 3,4dihydroisoquinoline hydrochloride and 28.0 g (0.2 mole) of 1-cyclohexen-1-yl ethyl ketone in 28 ml of ethanol is refluxed for 52 hours then poured into 300 ml of water and extracted with ether. The aqueous layer is separated and made basic by slowly adding ammonium hydroxide solution with stirring. Stirring is continued until a solid is formed after which the liquid is decanted. The solid is washed with water, dissolved in methylene chloride, dried over sodium sulfate and concentrated to an oil. The oil is dissolved in refluxing hexane, filtered and concentrated to a solid which is recrystallized from hexane-benzene to give 2,3,4,4a,6,7,11b,12,13,13a-decahydro-12-methyl-1H-dibenzo[a,f]-quinolizin-13-one, M.P. 144.5°-147.5° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33](=[O:34])[CH2:32][CH:29]5[CH2:30][CH2:31][O:26][CH2:27][CH2:28]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CC1CCOCC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (29.3 mg, 78.5%), MS (ISP) m/z=457.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 2-(tetrahydro-2H-pyran-4-yl)acetic acid.