Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:14][NH2:15])[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[CH:2]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH:37]=2)[C:34](O)=[O:35])[N:25]=1>>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:14][NH:15][C:34](=[O:35])[C:33]3[CH:37]=[C:29]([C:26]4[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=4)[CH:30]=[N:31][CH:32]=3)[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)[CH:2]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: CN1CCC(CN)(c2cccc(-c3ccccc3)c2)CC1
Product: CN1CCC(CNC(=O)c2cncc(-c3noc(C(F)(F)F)n3)c2)(c2cccc(-c3ccccc3)c2)CC1
Yield: 30 %

Procedure:
This compound was synthesized from (4-([1,1′-biphenyl]-3-yl)-1-methylpiperidin-4-yl)methanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (60 mg, yield 30%) as an off white solid. 1H NMR (400 MHz, MeOD) δ 9.32 (d, J=2.0 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.68-8.67 (t, J=2.0 Hz, 1H), 7.65 (m, 1H), 7.57-7.55 (m, 2H), 7.50-7.47 (m, 3H), 7.40-7.36 (t, J=7.4 Hz, 2H), 7.31-7.28 (m, 1H), 3.62 (m, 2H), 2.79-2.76 (m, 2H), 2.44-2.31 (m, 4H), 2.24 (m, 3H), 2.11-2.05 (m, 2H). MS (ESI) m/z: Calculated for C23H26F3N5O2: 521.20. found: 522.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[CH:12]=[C:11]([F:17])[C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.CC(C)(C)C(O)=O>>[F:15][C:14]1[C:13]([F:16])=[CH:12][C:11]([F:17])=[C:10]([F:18])[C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[CH:2][N:7]=1
Reactant: Fc1cc(F)c(F)c(Oc2ccnc(Cl)n2)c1F
Agent: CC(C)(C)C(=O)O
Product: Fc1cc(F)c(F)c(Oc2ccncn2)c1F
Temperature: 60 °C

Procedure:
To a mixture of 2-chloro-4-(2,3,5,6-tetrafluorophenoxyl)pyrimidine (compound no. C-2, 200 mg, 0.72 mmol) and 2,2-dimethylpropanoic acid (733 mg, 0.412 mL, 7.2 mmol, 10 eq.) was added the aromatic or heterocyclic amine (1.08 mmol, 1.5 eq.) and the mixture was heated to 60° C. for 2 h. The reaction mixture was partitioned between a mixture of water and diethyl ether. The organic layer was washed with water two times, aqueous 0,1M sodium hydroxide and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to yield light yellow solids which were triturated in a small amount of 50/50 diethyl ether/petroleum ether, filtered and dried to yield 2-(N-aryl/heterocyclyl-N—H/alkyl)-4-(2,3,5,6-tetrafluorophenoxyl)pyrimidine (compound no. 4) as white solids.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:8][CH:7]=1)=[O:5].[Na]>C(O)C>[C:15]([O:14][C:12]([NH:11][C:9]1[S:10][C:6]([C:4](=[O:5])[C:3]([OH:19])=[O:2])=[CH:7][N:8]=1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: [Na]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)C(=O)O)s1
Yield: 82.6 %

Procedure:
Methyl(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl)(oxo)acetate (1.14 g, 4 mmol) in ethanol (10 ml) was treated with sodium hydroxyde (2N, 4 ml, 8 mmol) for 3M minutes at room temperature. Ethanol was removed, the aqueous solution was acidified (pH 3). The solid was recovered, dried to give title product (900 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:10][C:9]2[NH:8][C:7](C(O)=O)=[C:6]([CH2:14][CH3:15])[C:5]=2[C:4](=[O:16])[CH2:3]1.O>C(O)(=O)C.Cl>[CH3:17][C:2]1([CH3:1])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:14][CH3:15])[C:5]=2[C:4](=[O:16])[CH2:3]1
Reactant: CCc1c(C(=O)O)[nH]c2c1C(=O)CC(C)(C)C2
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A suspension of 6,6-dimethyl-3-ethyl-4-oxo-4,5,6,7-tetrahydro- 1H-indole-2-carboxylic acid (2.5 g, 0.011 mol) in acetic acid (12 mL) and hydrochloric acid (10M; 0.64 mL) was heated at 100° C. for 45 min. After this time water (50 mL) was added, the cooling bath removed and the solution stirred at room temperature for 2 h. The precipitate was collected by filtration and the title pyrrole (1.76 g, 87%) isolated as a colourless solid. mp. 150° C.-152° C. C12H17NO requires: C, 75.35; H, 8.96; N, 7.32%. Found: C, 75.00; H, 8.88; N, 7.24%. 1H NMR (250 MHz, CDCl3) δ 1.10 (6H,s), 1.19 (3H,t,J=7.4 Hz), 2.32 (2H,s), 2.63 (2H,s), 2.75 (2H,d of q,J=7.4 and 1.0 Hz), 6.42 (1H,br s), 8.00 (1H,br s). MS (ES+) 192 (M+1).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:33][C:34]4[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[N:17][CH:18]=[C:19]([CH:21]([N:23]4[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]4)[CH3:22])[CH:20]=3)[N:12]=[C:11]([CH3:42])[N:10]=2)=CC=1.FC(F)(F)C(O)=O>>[CH3:41][O:40][C:37]1[N:36]=[CH:35][C:34]([NH:33][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:42])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH:21]([N:23]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:25][CH2:24]3)[CH3:22])=[CH:18][N:17]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(C)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
N,N-Bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (499.0 mg, 0.6744 mmol) was dissolved in trifluoroacetic acid (10.4 mL, 140 mmol) and the flask was fitted with a reflux condenser, placed in a preheated oil bath (75° C.) and stirred overnight. Then, the reaction was cooled to room temperature, concentrated, diluted with DCM (40 mL) and treated with saturated sodium bicarbonate, water, and 5N NaOH until the pH of the aqueous phase was about 7. Then, the layers were separated, and the aqueous phase was extracted with DCM and 10:1 DCM/MeOH. During these extractions, 5N NaOH was added to the aqueous phase to raise the pH from about 5 to about 11. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; 75:1 DCM/MeOH to 50:1 DCM/MeOH to 35:1 DCM/2N ammonia in MeOH to 20:1 DCM/2N ammonia in MeOH to 10:1 DCM/2N ammonia in MeOH) to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (241.9 mg, 72% yield) as a yellow powder. 1H NMR (CDCl3, 400 MHz) δ 11.68 (s, 1H), 8.71 (s, 1H), 8.36 (d, J=2.74 Hz, 1H), 8.27 (d, J=2.35 Hz, 1H), 8.13 (dd, J=8.80 Hz, 2.74 Hz, 1H), 6.79 (d, J=8.80 Hz, 1H), 5.42 (br s, 2H), 3.95 (s, 3H), 3.60-3.52 (m, 1H), 3.30-3.20 (m, 4H), 2.77 (s, 3H), 2.70-2.53 (m, 7H), 1.45 (d, J=6.06 Hz, 3H). m/z (ESI, +ve ion) 500 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:21][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 104.4 %

Procedure:
To a solution of 4-benzoylbenzoic acid (2.00 g) in trifluoroacetic acid (30 mL) was added dropwise triethylsilane (3.53 mL), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then n-hexane was added to the residue. The precipitate was collected by filtration, washed with n-hexane and dried under reduced pressure at 60° C. to give 4-benzylbenzoic acid (1.66 g). To an ice-cold suspension of lithium aluminium hydride (0.315 g) in tetrahydrofuran (45 mL) was added dropwise a solution of 4-benzylbenzoic acid (1.60 g) in tetrahydrofuran (30 mL), and the resulting mixture was stirred at room temperature for 4.5 hours. The reaction was quenched by sequential addition of water (0.320 mL), 15% aqueous sodium hydroxide (0.320 mL) and water (0.320 mL). The insoluble material was filtered out and the filtrate was concentrated under reduced pressure to give 4-benzylbenzyl alcohol (1.56 g). 4-Benzylbenzylalcohol (1.56 g) was dissolved in tetrahydrofuran (39 mL). After addition of phthalimide (1.39 g) and triphenylphosphine (2.68 g), diisopropylazodicarboxylate (40% toluene solution, 5.17 g) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give the title compound (1.87 g).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[O:12])[CH2:10][C:5]2=[N:4][CH:3]=1.C1C(=O)N([Cl:28])C(=O)C1>CN(C)C=O>[Cl:28][C:3]1[N:4]=[C:5]2[CH2:10][N:9]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[O:12])[CH2:8][CH2:7][N:6]2[C:2]=1[Cl:1]
Reactant: O=C(c1ccc(Cl)cc1Cl)N1CCn2c(Cl)cnc2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1Cl)N1CCn2c(nc(Cl)c2Cl)C1

Procedure:
3-Chloro-7-[(2,4-dichlorophenyl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (E44) (300 mg, 0.907 mmol) and NCS (133 mg, 0.998 mmol) were stirred at RT for 16 h in N,N-dimethylformamide (DMF) (2 mL). Solvents were removed in vacuo and the residue was purified by MDAP to afford desired product in 218 mg.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:29]([Si:33]([CH3:43])([CH3:42])[O:34][CH2:35][C:36]([CH3:41])([CH:38]1[CH2:40][O:39]1)[CH3:37])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[Si:33]([O:34][CH2:35][C:36]([CH3:37])([CH3:41])[CH:38]([OH:39])[CH2:40][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=2[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:8]1=[O:12])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:43])[CH3:42]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)C1CO1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(O)C(C)(C)CO[Si](C)(C)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 80 °C
Reaction time: 24 h
Yield: 42.6 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (2.0 g), tert-butyl(dimethyl) (2-methyl-2-oxirane-2-ylpropoxy)silane (3.75 g), potassium carbonate (1.38 g) and N,N-dimethylformamide (15 mL) was stirred at 80° C. for 24 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.36 g, 43%).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:25]CC)=[C:7]([S:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=2[OH:24])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C(O)=C(SC2C=C(C)C=C(C(C)(C)C)C=2OC)C=C(C)C=1)(C)(C)C.C(C1C(O)=C(SC2C=C(C)C=C(C(C)(C)C)C=2OCCC)C=C(C)C=1)(C)(C)C.C(C1C(O)=C(SC2C=C(C)C=C(C(C)(C)C)C=2O[Si](C)(C)C)C=C(C)C=1)(C)(C)C.C(C1C(O)=C(SC2C(C)=CC=CC=2C)C=C(C(C)(C)C)C=1)(C)(C)C>>[S:12]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=1[OH:24])[C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=1[OH:25]
Reactant: CCOc1c(Sc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Agent: CCCOc1c(Sc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Agent: COc1c(Sc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Agent: Cc1cc(Sc2cc(C)cc(C(C)(C)C)c2O[Si](C)(C)C)c(O)c(C(C)(C)C)c1
Product: Cc1cc(Sc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1

Procedure:
Preferably, the ligand is (3-tert-butyl-2-ethoxy-5-methylphenyl)(3-tert-butyl-2-hydroxy-5-methylphenyl)sulfide, (3-tert-butyl-2-hydroxy-5-methylphenyl)(3-tert-butyl-2-methoxy-5-methylphenyl)sulfide, (3-tert-butyl-2-hydroxy-5-methylphenyl)(3-tert-butyl-2-n-propoxy-5-methylphenyl)sulfide, (3-tert-butyl-2-hydroxy-5-methylphenyl)(3-tert-butyl-5-methyl-2-trimethylsiloxyphenyl)sulfide or (3,5-di-tert-butyl-2-hydroxyphenyl)(2,6-dimethylphenyl) sulfide. The most preferred ligand is (3-tert-butyl-2-hydroxy-5-methylphenyl)(3-tert-butyl-2-methoxy-5-methylphenyl)sulfide.
Reaction SMILES: [N:1]([C:4]([C:6]1[N:10]=[CH:9][O:8][N:7]=1)=[O:5])=[N+]=[N-].N[C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>C(Cl)(Cl)Cl>[C:12]12([NH:1][C:4]([C:6]3[N:10]=[CH:9][O:8][N:7]=3)=[O:5])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2
Reactant: [N-]=[N+]=NC(=O)c1ncon1
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: ClC(Cl)Cl
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1ncon1
Reaction time: 24 h
Yield: 27 %

Procedure:
3-Azidocarbonyl-1,2,4-oxadiazole (350 mg.) was added to a solution of 1-aminoadamantane (378 mg.) in chloroform (15 ml.) and the mixture was stirred for 24 hr. The chloroform solution was evaporated to dryness under reduced pressure and the residue was recrystallised from aqueous methanol to give title compound (167 mg.), m.p. 141°-142°, νmax. (EtOH) 230 nm (ε 3,910), λmax. (Nujol) 3392 (--NH--) 1692 and 1515 cm.-1 (CONH). Further examples provided in Table II were prepared by the following general methods:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1)[CH2:9][C:8]2([CH3:24])[CH3:23])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:10]2[CH2:9][C:8]([CH3:23])([CH3:24])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[NH:11]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccc(F)c(Cl)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)O)cc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 94.8 %

Procedure:
To a stirred mixture solution of 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (348.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (316.4 mg, 95%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=334.1.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH:11]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>CO>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH:11]=[C:21]([N+:18]([O-:20])=[O:19])[CH3:22]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=Cc1[nH]c2ccccc2c1C)[N+](=O)[O-]

Procedure:
A mixture of 3-methyl-2-indolecarbaldehyde (7.0 g), ammonium acetate (1.4 g) and nitroethane (10.5 ml) in methanol (35 ml) was refluxed for an hour. After the solvent was removed, the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was pulverized with isopropyl ether to give 3-methyl-2-(2-nitro-1-propenyl)indole (4.29 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(F)cc2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(COC2CNCCC2c2ccc(F)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
130 mg (0.31 mmol) of tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-(4-methoxy-benzyloxy)-piperidine-1-carboxylate were dissolved in 5 ml of methanol, treated with 5 ml of a 2 N solution of hydrogen chloride in methanol and stirred at 50° C. for 4 hours. Subsequently, the mixture was partitioned between ethyl acetate and aqueous 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was distilled off under reduced pressure. For purification, the crude product was chromatographed on silica gel with a 10:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There were obtained 76 mg (78% of theory) of (3RS,4RS)-4-(4-fluorophenyl)-3-(4-methoxy-benzyloxy)-piperidine as a colourless oil. MS: 316 (M+H)+.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:15]2[N:16]=[CH:17][N:18]=[C:14]2[N:13]=[C:12]([OH:19])[C:11]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]#[N:34])=[CH:23][CH:22]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:11]2[C:12]([OH:19])=[N:13][C:14]3[N:15]([N:16]=[CH:17][N:18]=3)[C:10]=2[CH2:9][OH:8])=[CH:26][CH:25]=1)#[N:34]
Reactant: N#Cc1ccccc1-c1ccc(Cc2c(O)nc3ncnn3c2COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N#Cc1ccccc1-c1ccc(Cc2c(O)nc3ncnn3c2CO)cc1
Yield: 30.6 %

Procedure:
A solution of 9 g of the compounds prepared in Example 43 in 360 ml of acetic acid is reduced by catalytic hydrogenation in the presence of 1.8 g of 5% palladium-on-charcoal. The reaction is carried out at atmospheric pressure and at 50° C. The catalyst is filtered off on Celite 545 and washed with acetic acid and the filtrate is concentrated and then purified by chromatography on silica gel (eluent: chloroform 95%/methanol 5%) to give 4.5 g of the starting material and 2.2 g of 6-[(2'-cyanobiphenyl-4-yl)methyl]-5-hydroxy-7-hydroxymethyl-1,2,4-triazolo[1,5-a]pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[CH3:16][N:17]([CH:19]=[C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:9]1=[O:12])[CH3:18]
Reactant: CCOC(OCC)N(C)C
Reactant: Cc1ccc2c(c1)C(=O)CCC2
Product: Cc1ccc2c(c1)C(=O)C(=CN(C)C)CC2

Procedure:
3,4-Dihydro-2-dimethylaminomethylene-7-methyl-1(2H) naphthalenone was prepared from 7-methyl-1-tetralone (4.8 g, 30 mmol) and N,N-dimethyl-formamide diethyl acetal (15.4 ml, 90 mmol). The crude product was recrystallised from diethyl ether-hexane to give yellow crystals (4.64 g) m.p. 79-82° MS (ES+) 238 (MNa+, 6%), 216 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH:12]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:13].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:12]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:13]
Reactant: Oc1cccc(Cl)c1
Reactant: COC(=O)c1ccccc1C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C(C)Oc1cccc(Cl)c1
Yield: 88 %

Procedure:
A solution of 3-chlorophenol (8.2 g) in DMF (30 ml) was added dropwise to a stirred suspension of sodium hydride (1.3 g) in DMF (30 ml). An hour later, a solution of crude methyl 2-(1-bromoethyl)benzoate described above (12 g) in DMF was added with stirring. After stirring at room temperature for 2 hours, the resulting mixture was poured into water and extracted with ether. The ether extracts were washed successively with water (×2), aqueous sodium hydroxide (×2), and brine, then dried and concentrated to give methyl 2-[1-(3-chlorophenoxy)ethyl]benzoate (14.84 g, 88% pure by GC), as a yellow oil.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1.O=[C:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.CO.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[O:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([C@H:16]3[CH2:17][CH2:18][C@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:20][CH2:21]3)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: C1CN(C2CCOCC2)CCN1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCN(C3CCOCC3)CC2)CC1

Procedure:
To a solution of EXAMPLE 336B (1 g) and tert-butyl 4-oxocyclohexylcarbamate (0.877 g) stirred for 24 hours at room temperature in titanium(IV) isopropoxide (2.410 mL), methanol (2 mL) was added followed by careful addition of sodium borohydride (0.311 g). The reaction mixture was quenched with water, extracted with ether, dried and concentrated. The crude product was purified by flash chromotography (silica 80 g, 50%-100% acetone/hexanes) providing the product.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:15])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19]>>[C:1]([NH:4][CH:5]([CH3:15])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:17][C:18]([OH:20])=[O:19])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)CC(=O)O
Reactant: CC(=O)NC(C)Cc1ccc(C=O)cc1
Product: CC(=O)NC(C)Cc1ccc(C=CC(=O)O)cc1

Procedure:
The ester hydrochloride used as starting material is prepared in the following manner: N-acetyl-4-acetylamphetamino (m.p. 99°-100° C.) is oxidized to 4-(2-acetamidopropyl)-benzoic acid (m.p. 207°-208° C.), this is reduced to give 4-(2-acetamidopropyl)-benzyl alcohol (oil) which is then oxidized to 4-(2-acetamidopropyl)-benzaldehyde (m.p. 84°-86° C.) and this is condensed with malonic acid to give 4-(2-acetamidopropyl)-cinnamic acid (m.p. 207°-208° C.) which is hydrogenated to give β-[4-(2-acetamidopropyl)-phenyl]-propionic acid (m.p. 93°-96° C.). Subsequent acid hydrolysis gives the hydrochloride of β-[4-(2-aminopropyl)-phenyl]-propionic acid which is esterified to give the above-mentioned ethyl ester hydrochloride.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:16]=[CH:15][NH:14][N:13]=2)[N:7]=1.[H-].[Na+].[CH3:19]I>CN(C)C=O>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:16]=[CH:15][N:14]([CH3:19])[N:13]=2)[N:7]=1
Reactant: CI
Reactant: c1cc(-c2cc[nH]n2)nc(C2OCCO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(-c2cccc(C3OCCO3)n2)n1
Reaction time: 1 h

Procedure:
2.50 g of 2-[1,3]dioxolan-2-yl-6-(1H-pyrazol-3-yl)pyridine (11.5 mmol) dissolved in 4 ml of N,N-dimethylformamide are added dropwise to a suspension of 0.48 g of sodium hydride (20 mmol) in 4 ml of N,N-dimethylformamide. The reaction mixture is stirred for 1 hour under a nitrogen atmosphere and then 0.93 ml of methyl iodide (15 mmol) diluted in 1 ml of N,N-dimethylformamide is added dropwise to the reaction mixture. The solution is stirred for 12 hours at room temperature and then the mixture is poured in ice-cold water and the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: chloroform/methanol; 99:1). 0.83 g of a white solid is obtained.