Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[CH:21]([CH3:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)=[CH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl>[CH3:20][O:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([CH2:9][C:5]2[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[C:12]([CH:21]([CH3:29])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:13]=1
Reactant: COc1cc(C(=O)c2cnc(N)nc2N)c(C(C)Cc2ccccc2)cc1OC
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(Cc2cnc(N)nc2N)c(C(C)Cc2ccccc2)cc1OC
Temperature: 0 °C
Yield: 43.6 %

Procedure:
To a solution of (2,4-diamino-pyrimidin-5-yl)-[4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-phenyl]-methanone (0.413 g, 0.4 mmol) in 10 mL THF was added LiAlH4 (0.73 mL, 1.0 M in THF) over 5 min. After gas evolution ceased the mixture was warmed to reflux. After 3 h the mixture was cooled to 0° C. and quenched by the Fieser method. After 30 min the mixture was filtered through a pad of celite and concentrated in vacuo to give a crude white solid. To a solution of this solid in 5 mL CH2Cl2 was added trifluoroacetic acid (1.1 mL, 14.0 mmol) followed by triethylsilane (0.4 mL, 2.8 mmol). After 30 min 50 mL 10% K2CO3 was as added and the mixture was extracted with ethyl acetate and washed with brine. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (95:5 CH2Cl2) afforded 5-[4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-benzyl]-pyrimidine-2,4-diamine (0.066 g, 58%) as a white foam; melting point (HCl salt) 227.1-227-4° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH:20]([OH:22])[CH3:21])[CH:12]=1.C(N(CC)CC)C>O>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[CH:12]=1
Reactant: CC(O)CCCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 87 %

Procedure:
To a solution of oxalyl chloride (0.060 mL in 1 mL dry methylene chloride) at -78° C. was added a solution of methyl sulfoxide (0.075 mL in 0.25 mL methylene chloride) and the mixture stirred at low temperature for 18 minutes. A solution of 5-pyridin-3-yl-pentan-2-ol (71 mg in 1 mL methylene chloride) and the reaction allowed to proceed for 40 minutes after which time 0.35 mL triethylamine were added and the mixture allowed to warm to room temperature. After 35 minutes, water was addded and the mixture extracted with methylene chloride. The organic portion was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (methylene chloride:methanol, 96:4) gave the title compound (61 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)[C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2
Reactant: Fc1ccc(CBr)cc1
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2

Procedure:
The title compound was prepared from methyl 3-benzyloxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate using a procedure similar to that found in Example 13, Step 1, except that 4-fluorobenzyl bromide was used in place of iodomethane. Purification was achieved by flash column chromatography on silica gel using a gradient elution of 0-6% MeOH/CH2Cl2, and collection and concentration of appropriate fractions afforded the title product. 1H NMR (400 MHz, CDCl3) δ 7.57-7.55 (d, 2H), 7.38-7.29 (m, 5H), 7.08-7.03 (m, 2H), 5.40 (s, 2H), 4.74 (s, 2H), 4.33-4.30 (t, 2H), 3.93 (s, 3H), 3.63-3.59 (t, 2H); ES MS (M+1)=410.
Reaction SMILES: [Br:1]/[CH:2]=[C:3]1/[CH:4]([OH:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/1.C[C@H](N)C1C=CC=CC=1>>[Br:1]/[CH:2]=[C:3]1/[C@@H:4]([OH:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/1
Reactant: OC1CCCCCC/C1=C\Br
Agent: C[C@H](N)c1ccccc1
Product: O[C@H]1CCCCCC/C1=C\Br

Procedure:
This alcohol was resolved, as in the previous examples, by conversion to the half ester XXXIc and then to the salt with L-(-)-α-methylbenzylamine. Three recrystallizations of this salt from 2-propanol gave 37 g, mp 144°-145° C, αD = +36.0 (c 2.0, CH3OH).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([S:16]CC2C=CC(OC)=CC=2)([CH3:15])[CH3:14])[CH2:11][C@H:10]([CH2:26][S:27]CC2C=CC(OC)=CC=2)[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O>[CH2:1]([N:8]1[C@H:12]([C:13]([SH:16])([CH3:15])[CH3:14])[CH2:11][C@H:10]([CH2:26][SH:27])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CSC[C@H]2C[C@@H](C(C)(C)SCc3ccc(OC)cc3)N(Cc3ccccc3)C2=O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CC(C)(S)[C@@H]1C[C@H](CS)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
To a stirred solution of cis-N-benzyl-4-[1-(4-methoxybenzylthio)-1-methylethyl]-2-(4-methoxybenzylthiomethyl )-4-butanelactam (compound No.14-1, 500 mg) in trifluoroacetic acid (4 ml), thioanisol (0.66 ml) and trifluoromethanesulfonic acid (0.50 ml) were added. After stirring for 2 hours at room temperature, the mixture was poured into a mixture of ice and saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and then saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was dissolved in ethanol (3 ml). To the solution sodium borohydride (20 mg) was added and the mixture was stirred for 30 minutes at room temperature. 1N hydrochloric acid was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 50 mg (18%) of the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[CH3:33]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:26][C:25]=1[CH3:33]
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cncnc1
Reactant: Cc1cc(B(O)O)ccc1Cl
Product: Cc1cc(-c2cc(NC(=O)c3cncnc3)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 39, using pyrimidine-5-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; LC-MS (UV peak area/ESI) 100%, 421.0698 (M−H)−.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][O:6][CH3:7])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[C:16]=[O:17]>C1(C)C(C)=CC=CC=1>[CH3:1][NH:2][C:3]([N:5]([O:6][CH3:7])[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[F:8])=[O:17])=[O:4]
Reactant: CNC(=O)NOC
Reactant: O=C=Nc1ccccc1F
Solvent: Cc1ccccc1C
Product: CNC(=O)N(OC)C(=O)Nc1ccccc1F

Procedure:
To 35 g (0.27 mol) of 1-methyl-3-methoxy urea in 150 ml xylene was added dropwise a solution of 37 g (0.27 mol) 2-fluorophenylisocyanate in 100 ml of xylene. The reaction mixture was refluxed for 4 hours. The reaction mixture was filtered while warm to remove a small amount of triethylamine hydrochloride (impurity in the urea reactant). The filtrate was evaporated to give the biuret product as a solid (m.p. 144°-147° C after recrystallization from benzene). Elemental analysis for fluorine showed: calc. 7.88%, found 7.64%.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:15](Cl)=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[Cl:25]>>[Cl:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[NH:18][C:15]([C:2]1[S:1][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1)=[O:16]
Reactant: Nc1ccncc1Cl
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Product: O=C(Nc1ccncc1Cl)c1cc2c(s1)-c1ccccc1OCC2

Procedure:
Following Example 17, 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonylchloride and 4-amino-3-chloropyridine were reacted to give N-(3-chloropyridin-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide. To a solution of N-(3-chloropyridin-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (0.340 g, 0.953 mmol) in DMF (5 mL, 60 mmol) was added sodium hydride (0.0381 g, 0.953 mmol). The reaction mixture was stirred at room temperature for about 10 min. followed by the addition of methyl iodide (65.25 uL, 1.048 mmol) and stirred at room temperature for another 1 hr. An aliquot was analyzed by LC/MS showing clean conversion to desired product. The reaction mix was diluted with EtOAc and washed with water/saline, dried (Na2SO4) then concentrated to a residue which was analyzed by LC/MS and 1H NMR. The crude product was taken into DMF at about 100 mg/mL, but was not totally soluble. Soluble material was purified by preparative RP-HPLC to give 184 (yield 30% of theoretical). MS: (ESI+) 372.2
Reaction SMILES: [CH:1]1([CH:4]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[O:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=2[O:14][CH3:15])[CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C.O.O.O.O.O.O.[Co](Cl)Cl>[CH:1]1([CH:4]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[O:5][C:6]2[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][C:7]=2[O:14][CH3:15])[CH2:3][CH2:2]1
Reactant: COc1ccc(C(Oc2ccc(C#N)cc2OC)C2CC2)cn1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(Oc2ccc(CN)cc2OC)C2CC2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a stirred 0° C. solution of 4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzonitrile (2.50 g, 8.06 mmol) in ethanol (20 mL) was added cobalt(II) chloride hexahydrate (2.20 g, 9.25 mmol) in small portions. The resulting mixture was allowed to stir at 0° C. After 30 min, the mixture was treated with sodium borohydride (1.80 g, 47.58 mmol) added in small portions. The mixture was allowed to warm to room temperature. After 30 min, the mixture was filtered through Celite, and the filtercake was washed with ethanol (20 mL). The filtrate was concentrated to provide 2.50 g (99%) of (4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxyphenyl)methanamine as a colorless oil.
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:27])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:27])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: CCCCCCNC(=O)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCNC(=O)Oc1ccc2c(c1)CCCN2

Procedure:
A mixture of hexyl-carbamic acid 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-yl ester (0.732 g., 2 mmol) and 5% Pd—C (0.08 g.) in absolute ethanol (20 ml) was shaken in a par apparatus at room temperature (38° C.) under 50 psi pressure of hydrogen for 4 hours. Pd—C was then discarded through filtration. The reaction mixture was concentrated under vaccum and the separated solid was washed with chloroform (2×5 ml) to give 2a; yield: 0.60 g. (64.1%), m.p.: 100° C., C16H24N2O2; 1H NMR δ ppm (CDCl3): 0.88 (bs, 3H), 1.25-1.30 (m, 5H), 1.51-1.58 (m, 3H), 1.85-1.97 (m, 3H), 2.74 (t, 2H), 3.16-3.29 (m, 4H), 3.6 (bs, 1H), 4.87 (bs, 1H), 6.39-6.4 (m, 1H), 6.68-6.71 (m, 2H), IR vmax (KBr) (cm−1): 770, 816, 886, 956, 1006, 1101, 1152, 1221, 1243, 1311, 1354, 1505, 1626, 1702, 1848, 2372, 2856, 2929, 3392, 3760, 3809, 7874, MS: m/z: 277 (M+).
Reaction SMILES: [CH2:1]([N:4]([CH2:60][CH2:61][CH3:62])[C:5]([C:7]1[CH:8]=[C:9]([CH:52]=[C:53]([C:55]2[O:56][CH:57]=[CH:58][N:59]=2)[CH:54]=1)[C:10]([O:12][C@H:13]([CH2:32][N:33](C(OC(C)(C)C)=O)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1)[C@@H:14]([NH:24]C(OC(C)(C)C)=O)[CH2:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[O:11])=[O:6])[CH2:2][CH3:3].[ClH:63].O1CCOCC1>>[ClH:63].[ClH:63].[CH2:60]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:52]=[C:53]([C:55]2[O:56][CH:57]=[CH:58][N:59]=2)[CH:54]=1)[C:10]([O:12][C@H:13]([CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:43])([F:44])[F:42])[CH:36]=1)[C@@H:14]([NH2:24])[CH2:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[O:11])=[O:6])[CH2:61][CH3:62]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O[C@H](CN(Cc2cccc(C(F)(F)F)c2)C(=O)OC(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)cc(-c2ncco2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCN(CCC)C(=O)c1cc(C(=O)O[C@H](CNCc2cccc(C(F)(F)F)c2)[C@@H](N)Cc2cc(F)cc(F)c2)cc(-c2ncco2)c1
Reaction time: 1 h

Procedure:
(1R,2S)-2-[(tert-butoxycarbonyl)amino]-1-({(tert-butoxycarbonyl)[3-(trifluoromethyl)benzyl]amino}methyl)-3-(3,5-difluorophenyl)propyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (482 mg, 0.55 mmole) is dissolved in hydrochloric acid/dioxane (4N, 3 ml) is stirred for 1 hour at 20-25°. The solvent is then removed under reduced pressure to give the title compound, MS (MH+) 673.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[CH3:37][O:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1>>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[C:7]([C:9]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=3[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Product: COc1cccc(-c2cccc(CN(C(=O)c3cc(C(=O)O)c(C(=O)O)cc3C(=O)O)[C@H]3CCCc4ccccc43)c2)c1

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 3-methoxyphenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: COC1C=C(N)C=C[C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16]O[CH2:14][CH2:13]1.[CH2:19]([OH:21])[CH3:20]>[Pd]>[CH3:8][O:9][CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:20]([CH:19]=[O:21])[CH2:16][CH2:17]1
Reactant: COc1cc(N)ccc1OCCN1CCOCC1
Reactant: CCO
Agent: [Pd]
Product: COCCN1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[2-(2-Methoxy-4-nitro-phenoxy)-ethyl]-morpholine To a solution of (1-(2-hydroxyethyl)-morpholine) (1.94 ml, 16 mmol) in dimethylformamide was added sodium hydride [60% dispersion in oil] (544 mg, 16 mmol). After stirring at room temperature for 10 min, a solution of (1-chloro-2-methoxy-4-nitro-benzene) (3 g, 16 mmol) in dimethylformamide (10 ml) was added dropwise. The reaction mixture was left stirring at room temperature for 16 hours, concentrated, then the residue dissolved in ethyl acetate and washed with water. The organic phase was dried with magnesium sulphate, concentrated and the residue purified by column chromatography on silica gel to afford the title compound; MS(ES+) m/e 283 [M+H]+. Step 2. 3-Methoxy-4-(2-morpholin-4-yl-ethoxy)-phenylamine To a solution of the product of Step 1 (2.3 g, 8.6 mmol) in ethanol (100 ml) was added 10% palladium on charcoal (50 mg). The mixture was then stirred at room temperature under an atmosphere of hydrogen for 16 hours, filtered through celite and concentrated to give the title compound; MS(ES+) m/e 252 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:7]([CH3:14])[CH2:6][C:5]1([CH3:16])[CH3:15].[C-:17]#[N:18].[Na+].C(OCC)C>CS(C)=O>[C:17]([CH2:2][CH2:3][N:4]1[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:7]([CH3:14])[CH2:6][C:5]1([CH3:16])[CH3:15])#[N:18]
Reactant: [C-]#N
Reactant: CC1CC(C)(C)N(CCCl)C2CCCCC12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC1CC(C)(C)N(CCC#N)C2CCCCC12
Temperature: 95 °C
Reaction time: 2.5 h

Procedure:
1-(2'-cyanoethyl)-2,2,4-trimethyl decahydroquinoline was prepared via the post-reaction of the above chloroethyl substituted compound. 61.0 grams (0.25 mole) of 1-(2'-chloroethyl)-2,2,4-trimethyl decahydroquinoline dissolved in 50 milliliters of methyl sulfoxide was added dropwise over a period of 40 minutes at room temperature to a prepared solution of 12.25 grams (0.25 mole) of sodium cyanide in 150 milliliters of methyl sulfoxide. The mix was then heated to 95° C. and stirred for 2.5 hours. The reaction mixture was then cooled, poured into 500 milliliters of ice water, diethyl ether was added, the organic layer separated out. The aqueous layer was washed with four 100 milliliter portions of diethyl ether and the ether washes combined with the original organic layer. The solution was then concentrated and distilled using a 6" Vigreaux column to yield 43.0 grams of a liquid product boiling at 134°-136° C. at 3.3 mm Hg. The infrared spectrum of the product is consistent with the desired compound, 1-(2'-cyanoethyl)-2,2,4-trimethyl decahydroquinoline. Calculated values for the formula C15H26N2 are 76.87% carbon, 11.18% hydrogen, and 11.95% nitrogen and found contents were 76.71% carbon, 11.02% hydrogen, and 11.15% nitrogen.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[O:15][C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][N:18]=3)[CH:5]=[CH:4][C:3]1=2.[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[O:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[CH2:21][CH2:20]4)=[CH:17][N:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3ncc(C4CCNCC4)o3)ccc21
Reactant: O=CCCCCO
Product: CC1(C)CCC(C)(C)c2cc(-c3ncc(C4CCN(CCCCCO)CC4)o3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 150 mg (0.44 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxazol-5-yl]piperidine and 91 mg (0.89 mmol) of 5-hydroxypentanal. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20]C(=O)OC(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:30][O:31][C:32]1[N:36]([CH3:37])[N:35]=[C:34]([CH3:38])[C:33]=1[CH:39]=O>>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[C:10]1[CH:28]=[CH:29][C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:39][C:33]3[C:34]([CH3:38])=[N:35][N:36]([CH3:37])[C:32]=3[O:31][CH3:30])[CH2:6][CH2:5]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: COc1c(C=O)c(C)nn1C
Product: COc1c(CN2CCC(c3ccc(C(=O)Nc4ccccc4N)cc3)CC2)c(C)nn1C
Yield: 30.8 %

Procedure:
Using an analogous procedure to that described in Example 3, tert-butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 1 below; 200 mg, 0.51 mmol) was reacted with 5-methoxy-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (92.6 mg, 0.60 mmol) to give the title compound (68 mg, 36%); NMR Spectrum: (DMSO d6) δ 1.63 (m, 2H), 1.78 (m, 2H), 2.00 (m, 2H), 2.06 (s, 3H), 2.57 (m, 1H), 2.94 (m, 2H), 3.25 (s, 2H), 3.50 (s, 3H), 3.99 (s, 3H), 4.86 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.97 (m, 1H), 7.17 (d, 1H), 7.37 (d, 2H), 7.91 (d, 2H), 9.55 (s, 1H); Mass Spectrum: M+H+434.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][N:11]=1.[I:19]I.O>C1COCC1>[F:9][C:10]1[C:15]([I:19])=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][N:11]=1
Reactant: CC(C)c1ccc(F)nc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cnc(F)c(I)c1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 9.2 mL of LDA (lithium diisopropylamide) (2.0M solution in THF/heptane/ethylbenzene) in 20 mL of THF at −78° C. was added 2-fluoro-5-isopropylpyridine in 40 mL of THF dropwise over a period of 20 min. After 30 min. 4.39 g (17.3 mmol) of iodine in 25 mL of THF was added. After 2 h at −78° C. with the light off, 20 mL of water was added, and the cold bath was removed. Water (80 mL) was added and 9 g of sodium thiosulfate was added in 3 portions. Diethyl ether was added, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% Et2O/hexanes) provided 1.83 g of 2-fluoro-3-iodo-5-isopropylpyridine with some impurity.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.[CH3:20][NH:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:9]=[C:8]([N:21]([CH3:20])[C@@H:22]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:23]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: N#Cc1ccc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ccc(C#N)c(Cl)n1)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
To a solution of 2,6-dichloronicotinonitrile (2.2 mmol) and DIPEA (10 mmol) in DMF (10 mL) was added (R)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate with stirring at room temperature. The reaction mixture was stirred at 100° C. overnight. Then the mixture was diluted with EtOAc, washed 3 times with water, dried, filtered and concentrated. The crude product was purified by flash chromatography to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH:12]([CH:15]([OH:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH:12]([CH:15]([OH:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:13][OH:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCCCCCCCCCCCCCC(O)C(N)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCC(O)C(CO)Nc1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Yield: 25.7 %

Procedure:
13 g (0.092 mol) of 4-fluoronitrobenzene, 30 g (0.099 mol) of 2-aminooctadecane-1,3-diol and 11 g (0.104 mol) of sodium carbonate were introduced into a 250 ml reactor equipped with a condenser. The reaction mixture was maintained at 120° C. for 3 hours. 200 ml of water were added slowly to the reaction medium, which was then poured into 500 ml of ice-cold water. The precipitate formed was filtered off on a sinter funnel and dried under vacuum at 50° C. in the presence of P2O5. After recrystallization twice from ethanol, 10 g of yellow powder were isolated.