Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[NH:23][NH2:24].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(O)(=O)C.C(OCC)C>[C:27]([O:26][C:22]([NH:23][NH:24][CH:2]1[CH2:7][CH2:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)C1(c2ccc(C(F)(F)F)cc2)CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1(c2ccc(C(F)(F)F)cc2)CCC(NNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 53.7 %

Procedure:
Methyl 4-oxo-1-(4-trifluoromethylphenyl)cyclohexanecarboxylate (100 mg) and tert-butyl carbazate (66 mg) were dissolved in a mixed solvent of THF (6 mL) and acetic acid (3 mL). After stirring at room temperature for 50 minutes, sodium cyanoborohydride (31.4 mg) was added. After further two hours, sodium cyanoborohydride (31.4 mg) was added and the mixture was stirred at room temperature for one hour. Diethyl ether and a saturated sodium bicarbonate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with a saturated sodium bicarbonate solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (74.5 mg). The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH:6]1[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])(O)[C:9]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[C:8]=2[O:7]1.C(=O)([O-])O.[Na+]>C1COCC1.C(O)=O>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[O:7][C:8]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:9]=2[C:10]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COCOCC1Oc2c(OC)cccc2C1(O)CC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=CO
Product: COCOCc1oc2c(OC)cccc2c1CC(=O)OC
Yield: 84.6 %

Procedure:
Methyl (2,3-dihydro-2-methoxymethoxymethyl-3-hydroxy-7-methoxybenzofuran-3-yl)acetate (990 mg) was dissolved in THF (25 ml) and formic acid (15 ml), and the obtained solution was stirred at room temperature for 15 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and with saturated brine and dried over magnesium sulfate. Magnesium sulfate was removed by filtration and the solvent was evaporated off. The residue was purified by column chromatography (solvent: n-hexane/ethyl acetate=1/1) to obtain the desired compound (789 mg, yield: 75%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:46]1([C:52]2[CH:59]=[CH:58][CH:57]=[CH:56][C:53]=2[C:54]#[N:55])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>C(Cl)Cl.C(N(CC)CC)C>[C:17]([O:16][C:14](=[O:15])[NH:13][CH:11]1[CH2:10][CH:9]([C:21]([N:49]2[CH2:48][CH2:47][N:46]([C:52]3[CH:59]=[CH:58][CH:57]=[CH:56][C:53]=3[C:54]#[N:55])[CH2:51][CH2:50]2)=[O:22])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12]1)([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
The mixture of 1-benzyl-4-tert-butoxycarbonylamino-pyrrolidine-2-carboxylic acid, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride, N-hydroxybenzotriazole, 2-piperazin-1-yl-benzonitrile and triethylamine in DCM is stirred overnight. The crude product is purified to afford {1-benzyl-5-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-pyrrolidine-3-yl}carbamic acid tert-butyl ester (41).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:20]C)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[CH:11]=1>ClCCl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:20])=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[CH:11]=1
Reactant: COc1ccc(Cl)cc1-c1cccc(C#N)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cccc(-c2cc(Cl)ccc2O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of boron tribromide (1M in dichloromethane, 6 ml) was added to a stirred solution of the product from step (i) in dichloromethane (10 ml) at 0° C. After 15 min the mixture was warmed to room temperature, stirred for 16 h then poured onto ice. The mixture was extracted with dichloromethane then ethylacetate, the organics combined, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 30-70% diethylether/isohexane. Yield 0.415 g
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.B(F)(F)F.CCOCC.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[C:3]2[O:4][C:5]3[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:7](=[O:9])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1Br
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=c1c2ccccc2oc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution of 2-(2-bromophenoxy)-benzoic acid 2j (11.8 g, 40.3 mmol) in dichloromethane (200 mL) was added trifluoroacetic anhydride (6.3 mL, 44.6 mmol), and the mixture was stirred for 30 min at rt. Boron trifluoride etherate (0.51 mL, 4.03 mmol) was added, and the mixture was stirred for 2 h at rt. The mixture was cooled in an ice bath, and a 3N sodium hydroxide solution (100 mL) was added under vigorous stirring. The organic layer was separated, washed with water and brine, dired over magnesium sulfate, filtered, and evaporated. The residue was purified over silica gel using dichloromethane as eluent. The desired fractions were collected, and evaporated to yield 10.18 g (91.8%) of title compound 3j.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][CH:24]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[CH3:25])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:32][C:33]([CH3:35])=O>CO.[Pd]>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][CH:24]([CH:26]5[CH2:31][CH2:30][N:29]([CH:33]([CH3:35])[CH3:32])[CH2:28][CH2:27]5)[CH3:25])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CCNCC1
Reactant: CC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
A mixture of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-(1-piperidin-4-ylethoxy)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (211 mg, 0.50 mmol), acetone (6 mL) and 10% Pd/C (150 mg) in MeOH (2 mL) was stirred under an atmosphere of H2 at RT for 16 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, on a gradient 10-90%, 0.1% HCO2H acetonitrile/water) to afford 143 (161 mg, 69%). LCMS: RT 3.08 [M+H]+ 465.4. 1H NMR (DMSO, 400 MHz): δ 8.29 (1H, d, J=8.96 Hz), 8.23 (1H, s), 7.90 (1H, d, J=0.64 Hz), 7.85 (1H, s), 6.77 (1H, dd, J=8.99, 2.54 Hz), 6.57 (1H, d, J=2.51 Hz), 5.93-5.85 (1H, m), 4.48 (4H, s), 4.38-4.31 (1H, m), 2.97 (2H, d, J=11.01 Hz), 2.87-2.86 (1H, m), 2.30 (2H, t, J=11.50 Hz), 1.84 (1H, d, J=12.83 Hz), 1.67-1.63 (2H, m), 1.47 (6H, d, J=6.60 Hz), 1.44-1.29 (1H, m), 1.21 (3H, d, J=6.10 Hz), 1.03 (6H, d, J=6.56 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](N)=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][OH:16]>>[CH3:15][O:16][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CO
Reactant: NC(=O)Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: COC(=O)Cc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 4-chloro-3-nitrophenylacetamide (2.00 g, 9.32 mmol) in methanol (40 mL) was treated with Amberlyst® 15 ion exchange resin (15.00 g). The resulting reaction mixture was heated under reflux for 64 h. The reaction mixture was allowed to cool to 25° C. and then filtered to remove the Amberlyst® 15 ion exchange resin. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 4-chloro-3-nitrophenylacetic acid methyl ester (1.91 g, 89%) as a yellow oil: EI-HRMS m/e calcd for C9H8ClNO4 (M+) 229.0142, found 229.0146.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[F:24].O>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[O:12][CH2:11][CH:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:13][O:14]2)=[CH:18][C:17]=1[F:24]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: CCCC1CCC(C(CO)CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H](C2COC(c3ccc(Br)c(F)c3)OC2)CC1

Procedure:
A solution of 4.0 g (0.02 mol) of 2-(4'-propylcyclohexyl)propane-1,3-diol, 5.1 g (0.025 mol) of 4-bromo-3-fluorobenzaldehyde, and 0.2 g of TsOH in 100 cm3 of dichloromethane was refluxed over a hot water bath fitted with a Dean-Stark trap for 3 hours and the water formed was continuously removed from the reaction system. The resulting solution was washed with water and dichloromethane was distilled off. The residue was recrystallized from acetone to yield 6.2 g (0.016 mol) of 2-(4'-bromo-3'-fluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane. This compound contained about 10% of the cis isomer of the 1,3-dioxane ring.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[N:16]([CH3:22])[N:17]=[C:18]([CH3:21])[C:19]=1[F:20])(C)(C)C>C(Cl)Cl>[F:20][C:19]1[C:18]([CH3:21])=[N:17][N:16]([CH3:22])[C:15]=1[NH2:14]
Reactant: Cc1nn(C)c(NC(=O)OC(C)(C)C)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C)c(N)c1F
Reaction time: 24 h

Procedure:
TFA (170 mmol) was added to a solution of (4-fluoro-2,5-dimethyl-2H-pyrazol-3-yl)-carbamic acid tert-butyl ester (Step BH2) (22.68 mmol) in CH2Cl2 (50 mL) at rt. After stirring for 24 h, the reaction mixture was quenched with 2N aqueous NaOH and extracted with CH2Cl2 (3×). The combined organic phases were dried (Na2SO4), filtered and concentrated to afford the title compound as a bright yellow solid which was used in the next step without further purification. ESI-MS: tR=0.38 min, [M+H]+ 130 (LC-MS 1).
Reaction SMILES: [N:1]1([C:7]2[C:12]3[CH:13]=[CH:14][S:15][C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O=[CH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]1>>[S:15]1[C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]4)[CH2:5][CH2:6]3)[C:12]=2[CH:13]=[CH:14]1
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: c1cc2sccc2c(N2CCNCC2)n1
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1

Procedure:
The title compound, light brown solid (114 mg, 43%), MS (ISP) m/z=387.1 [(M+H)+], was prepared in analogy to example 1 from commercially available 4-piperazine-1-yl-thieno[3,2-c]pyridine [CAS-Nr. 106261-27-2] (150 mg, 0.68 mmol) and trans-N-[4-(2-oxo-ethyl)-cyclohexyl]-acetamide [CAS-Nr. 946599-01-5, WO 2007/093540] (125 mg, 0.68 mmol). Purification was performed by flash chromatography over silica gel (CH2Cl2/MeOH/25% NH3 aq 140:10:1).
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[C@@H:24]([F:25])[CH2:23][C@H:22]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C@@H:21]1[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].OS([O-])(=O)=O.[K+]>C1COCC1>[F:25][C@H:24]1[CH2:23][C@H:22]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C@H:21]([CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])[C@H:20]1[CH2:19][OH:18]
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](F)C[C@@H]1OC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CO)[C@@H](F)C[C@@H]1OC1CCCCO1
Reaction time: 4 h
Yield: 64.4 %

Procedure:
To a stirring solution consisting of (Z)-isopropyl 7-((1R,2S,3S,5S)-2-((tert-butyldiphenylsilyloxy)methyl)-3-fluoro-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (prepared in Step E, 2.7 g, 52 mmol) in anhydrous THF (500 mL) was slowly added a solution consisting of 1 M TBAF in THF (157 mL). The reaction mixture was stirred for 4 hours, monitoring by TLC. The reaction mixture was acidified with 5% KHSO4, extracted into ethyl acetate, washed with brine, and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel, eluted with hexanes-ethyl acetate (3:1) to afford the title intermediate 12.94 g, 64%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[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][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:50]([NH:60][CH2:61][C:62](O)=[O:63])([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]>>[C:50]([NH:60][CH2:61][C:62]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[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][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:63])([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-octadecanamide and N-carbobenzoxy-glycine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][S:20][C:16]1[CH:15]=[C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CSc1cccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1cccc(C2=CCNCC2)c1

Procedure:
4-Hydroxy-4-(3-methylsulfanyl-phenyl)-piperidin-1-carboxylic acid tert-butyl ester (3.97 g) was dissolved in CH2Cl2 (500 ml) and trifluoroacetic acid (80 ml) was added in one portion. The mixture was refluxed for one hour and then washed with two portions of 10%-Na2CO3, dried (MgSO4), filtered and evaporated to dryness. Yield 2.07 g. MS m/z (relative intensity, 70 eV) 205 (M+, 73), 158 (44), 129 (95), 128 (80), 82 (bp).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH3:29][N:30]([CH3:44])[C:31]([CH3:43])([CH3:42])[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>>[CH3:29][N:30]([CH3:44])[C:31]([CH3:43])([CH3:42])[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:36][CH:35]=1
Reactant: CCNc1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C)C(C)(C)COc1ccc(C=O)cc1
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC(C)(C)N(C)C)cc2)c1
Yield: 111.6 %

Procedure:
Synthesized from pivalic acid (S)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (34 mg) and 4-(2-dimethylamino-2-methylpropoxy)benzaldehyde (100 mg) according to an analogous synthetic method to Example 264 described below and purified by LC-MS, the title compound (50 mg) was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20].Cl>O1CCCC1>[CH2:20]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCCC(C(=O)OCC)C(=O)OCC
Reaction time: 0.25 h

Procedure:
To 120 ml of dry tetrahydrofuran (THF) was added 4.9 g of 60% sodium hydride, and 29.5 g of diethyl malonate was added dropwise with stirring under ice-cooling. After addition, stirring was continued for 15 minutes, and then g of 6-bromo-1-hexen was added to the mixture and heated to reflux for 21 hours. The reaction solution was cooled, poured into ice-cold water, neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=20:1) to provide 14.5 g of the objective compound as yellowish oil.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][C:7]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[O:10]2)[CH2:6][CH2:5]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH:4]1[CH2:5][CH2:6][C:7]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[O:10]2)[CH2:8][CH2:9]1
Reactant: [N-]=[N+]=NC1CCC2(CC1)OC(=O)c1ccccc12
Agent: [Pd]
Solvent: CO
Product: NC1CCC2(CC1)OC(=O)c1ccccc12
Reaction time: 1 h
Yield: 112.5 %

Procedure:
A mixture of 4′-azido-3H-spiro[2-benzofuran-1,1′-cyclohexan]-3-one (90 mg, 0.36 mmol) in methanol (5 mL) with 10% palladium on charcoal (30 mg) was stirred under hydrogen atmosphere (balloon) for 1 hour. After filtration, the solution was concentrated to yield 88 mg of 4′-amino-3H-spiro[2-benzofuran-1,1′-cyclohexan]-3-one (yield: 90%).
Reaction SMILES: [O:1]=[C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[BH4-].[Na+]>CO>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:2]([OH:1])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: O=C(COC1CCCCO1)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(COC1CCCCO1)c1ccccn1
Reaction time: 2.5 h
Yield: 72.4 %

Procedure:
To a stirred solution of 2-oxo-2-pyridin-2-yl-O-(tetrahydro-2H-pyran-2-yl)ethanol (1.15 g, 0.00520 mol) in methanol at 0° C. is added sodium borohydride (0.195 g, 0.00515 mol) in portions. The reaction is stirred for 2.5 hours and rotary evaporated to dryness. The residue is dissolved in ethyl ether, washed with brine (3×), dried (Na2SO4), and rotary evaporated. The residue is purified by chromatography on silica gel (50 g, 230-400 mesh), eluting with hexanes-ethyl acetate (1:1) to give 0.84 g of (±)-1-pyridin-2-yl-2-(tetrahydro-2H-pyran-2-yloxy)-ethanol as a pale yellow oil. MS-APCI m/z 224 [M−H]+. 4. (±)-6-(2-Tetrahydro-2H-1-pyran-2-yloxy-1-(2-pyridyl)ethoxy)-5-(2-phenylethyl)-2,3,4-trihydronaphthalen-1-one
Reaction SMILES: [NH2:1]/[C:2](=[N:4]\[O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=1)[C:11]([O:13][CH3:14])=[O:12])=O)/[CH3:3]>C1(C)C=CC=CC=1>[CH3:3][C:2]1[N:1]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])[O:5][N:4]=1
Reactant: COC(=O)c1ccnc(C(=O)O/N=C(/C)N)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2nc(C)no2)c1

Procedure:
A solution of (Z)-methyl 2-((1-aminoethylideneaminooxy)carbonyl)isonicotinate in toluene (1 L) was heated at reflux overnight. The obtained mixture was evaporated and purified by silica-gel column chromatography to afford methyl 2-(3-methyl-1,2,4-oxadiazol-5-yl)isonicotinate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2.S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:14][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)=[O:15]
Reactant: COc1ccc2cc(C(=O)O)ccc2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2cc(OC)ccc2c1
Temperature: 80 °C
Yield: 94 %

Procedure:
To a solution of 6-methoxy-naphthalene-2-carboxylic acid (1.01 g, 5 mmol) in methanol (10 mL), a catalytic amount of sulphuric acid was added. The mixture was then heated at 80° C. for 8 hours. Upon reaction completion (as monitored by LcMS), the solution was slowly cooled and the precipitation of the product was observed. Filtration of the white solid afforded 1.01 g (94% yield) of title compound
Reaction SMILES: [C:1]([C:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)=[O:6])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:36])=[C:24]([CH:35]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH3:36][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:14](=[O:16])[C:13]2[CH:17]=[C:9]([CH2:8][NH:7][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[O:6])[CH:10]=[CH:11][C:12]=2[Cl:18])=[CH:35][C:24]=1[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)=[O:26]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Cc1ccc(N)cc1C(=O)Nc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc(CNC(=O)C(C)(C)C)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
Prepared analogously to example 7 with 5-(tert-butylcarbonylamino)methyl-2-chloro benzoic acid (50 mg; 0.19 mmol); 5-amino-N-(4-bromo-phenyl)-2-methyl-benzamide (57 mg; 0.19 mmol); HATU (78 mg; 0.2 mmol) in TEA (77 μL; 0.56 mmol) and 5 mL THF.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2)=[C:4]([CH3:14])[N:3]=1.[CH3:15][NH2:16]>C(O)C>[CH3:14][C:4]1[N:3]=[C:2]([NH:16][CH3:15])[N:10]=[C:9]2[C:5]=1[NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2
Reactant: CN
Reactant: CCCc1nc2nc(Cl)nc(C)c2[nH]1
Solvent: CCO
Product: CCCc1nc2nc(NC)nc(C)c2[nH]1
Temperature: 110 °C

Procedure:
To a solution of 2-Chloro-6-methyl-8-propylpurine (from Step 1 of Example 32) (0.1 g, 0.47 mmol) in ethanol (2 ml) was added condensed methylamine (1 ml) at -20° C. The mixture was then placed in a steel-bomb and heated at 110° C. for 7 hours. The reaction was cooled and the mixture was concentrated in vacuo. The residue was partitioned between CHCl3 and water, and the organic layer was separated and dried over MgSO4. The crude product obtained after removal of the solvent was purified by flash-chromatography on silica-gel using 5% MeOH in CHCl3 giving the titled compound as an amorphous solid (0.115 g, quantitative). NMR(CDCl3): δ 1.03 (t, J=8 Hz,3H), 1.8 (q, J=8 Hz, 2H), 2.64 (s, 3H), 2.8 (t, J=8 Hz, 2H), 3.0 (d, J=5 Hz, 3 H), 5.1 (br s,1H). FAB-MS: m/e 206 (M+H).