Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4([C:31]([CH3:34])([CH3:33])[CH3:32])[O:30][CH2:29][CH2:28][O:27]4)=[C:20]([CH3:35])[CH:19]=3)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:36]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:31]([C:26]1([CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([C:13]([C:11]3[O:12][C:8]4[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:36][C:9]=4[CH:10]=3)([CH2:14][CH3:15])[CH2:16][CH3:17])=[CH:19][C:20]=2[CH3:35])[O:30][CH2:29][CH2:28][O:27]1)([CH3:32])([CH3:33])[CH3:34]
Reactant: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc2cc(C(=O)OC)ccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc2cc(C(=O)O)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A solution of 2-{1-[4-(2-tert-butyl-[1,3]dioxolan-2-ylmethoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-5-carboxylic acid methyl ester (1.51 g, 3.05 mmol) in methanol (5.0 mL) and THF (5.0 mL) and is treated with NaOH (2.0 M, 10 mL). The resulting mixture is stirred at RT for 2 h. The mixture is concentrated and neutralized with HCl (1 N) till pH˜3, and extracted with EtOAc (3×50 mL). The organic layer is dried over Na2SO4, concentrated to afford the title compound (1.43 g, 95%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17]O)[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:39]1[CH2:43][C:42](=[O:44])[NH:41][C:40]1=[O:45].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][N:41]3[C:42](=[O:44])[CH2:43][S:39][C:40]3=[O:45])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN1C(=O)CSC1=O
Temperature: 0 °C
Yield: 50.3 %

Procedure:
To a solution of 2-amino-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.13 g, 0.46 mmol) in tetrahydrofuran (3 ml) was added triphenylphosphine (0.13 g, 0.51 mmol), and thiazolidin-2,4-dione (60 mg, 0.51 mmol). The reaction mixture was cooled to 0° C. and diisopropylazodicarboxylate (99 μl, 0.51 mmol) was added via syringe. The resultant mixture was stirred for 18 hours, gradually warming to room temperature. The volatiles were evaporated in vacuo and the resulting oil was diluted in ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate (3×50 ml), brine (3×50 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to flash chromatography using a mixture of dichloromethane/methanol (9:1) as eluent. Pure fractions were collected (Rf=0.70) and the solvent evaporated in vacuo which afforded 89 mg (51%) of 2-amino-7-(2,4-dioxo-thiazolidin-3-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl)([O-:16])=[O:15]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N+:14]([O-:16])=[O:15])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(Cc2ccccc2[N+](=O)[O-])CC1

Procedure:
In 20 volume parts of ethanol is dissolved 2.16 parts of o-nitrobenzyl chloride, followed by the addition of 1.02 parts of N-methyl piperazine and 1.3 parts of potassium carbonate. The mixture is reacted under reflux for 1 hour. The reaction mixture is then filtered and the solvent is removed from the filtrate by distillation under reduced pressure. The residue is extracted with water-ether (1:1). The ethereal layer is taken and dried over anhydrous sodium sulfate and the solvent is then distilled off. This procedure gives N1 -methyl-N4 -(2-nitrobenzyl)piperazine as a brown colored oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15](=S)[NH:14][C:13]=2[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>C(OCCO)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15]([NH:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[N:14][C:13]=2[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: S=C1Nc2cc(OCc3ccccc3)ccc2Nc2ccccc21
Solvent: CCOCCO
Product: c1ccc(COc2ccc3c(c2)N=C(NCc2cccnc2)c2ccccc2N3)cc1
Yield: 47.7 %

Procedure:
A solution of 0.6 g (1.8 mmol) of 8-benzyloxy-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione in 10 mL 2-ethoxyethanol was treated with 0.4 mL (3.6 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then with saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure gave the crude product. After trituration with CHCl3 /hexane, recrystallization from MeOH gave 349 mg (47.8% yield) of the product as a yellow solid, mp 196-197° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =407.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:13].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:21][C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[O:24][N:23]=1>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH2:21][C:22]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)[O:24][N:23]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:13]
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: CCc1nc2c(Cl)c(Br)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2c(Cl)c(Br)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 90 °C
Yield: 138 %

Procedure:
5-Bromo-4-chloro-2-ethyl-1H-benzimidazole (0.100 g, 0.385 mmol), Cs2CO3 (0.188 g, 0.578 mmol), and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.152 g, 0.578 mmol) were combined in DMF (10 mL) and heated to 90° C. for 30 min. The reaction mixture was partitioned between Et2O and water. The combined organic portions were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) provided the title compound 0.258 g: MS (ESI) m/z 487 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cu](C#N)[C:12]#[N:13].O>CN(C=O)C>[C:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)#[N:13]
Reactant: N#C[Cu]C#N
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-3-nitropyridine (5 g, 31.6 mmol, 1.0 eq.) in 50 mL of DMF was added copper cyanide (2.47 g, 38 mmol, 1.2 eq.) and the reaction heated to 100° C. for 16 hours. The reaction mixture was cooled to ambient temperature and poured into 100 mL of water. The mixture was extracted with ethyl acetate (3×50 mL) and the combined ethyl acetate portions were dried over sodium sulfate and concentrated. The crude material was chromatographed on silica with 3:7 ethyl acetate/hexanes to give 2-cyano-3-nitropyridine as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:34](O)=[O:35])=[N:11][C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:71][CH2:72][C:73]1[CH:83]=[CH:82][C:81]([F:84])=[CH:80][C:74]=1[C:75]([O:77][CH2:78][CH3:79])=[O:76]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:34]([NH:71][CH2:72][C:73]2[CH:83]=[CH:82][C:81]([F:84])=[CH:80][C:74]=2[C:75]([O:77][CH2:78][CH3:79])=[O:76])=[O:35])=[N:11][C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCNc1nc(C(=O)O)c(OCc2ccccc2)c2ncccc12
Reactant: CCOC(=O)c1cc(F)ccc1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(F)ccc1CNC(=O)c1nc(NCCCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8-(Benzyloxy)-5-(6-(tert-butoxycarbonylamino)hexylamino)-1,6-naphthyridine-7-carboxylic acid (Example 1.2; 0.42 g; 0.85 mmol) was dissolved in dichloro methane (9 ml). DIPEA (0.58 ml; 3.42 mmol) and HBTU (0.39 g; 1.03 mmol) were added. The reaction mixture was stirred at room temperature during 5 min. Ethyl 2-(aminomethyl)-5-fluorobenzoate hydrochloride (Example 4; 0.24 g; 1.03 mmol) was added portionwise at room temperature. The mixture was stirred overnight at room temperature. The mixture was diluted with CH2Cl2 and washed with a saturated aqueous Na2CO3 solution (2×) and H2O. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromategraphy over silica gel (eluent: hexane/EtOAc 10:1 up to 1:1). The fractions were collected and the solvent evaporated.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[CH2:11]OS(C)(=O)=O)[CH:5]=[CH:4][N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C>COCCOC>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:11][C:10]2[CH:17]=[CH:18][CH:19]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:29][C@@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CS(=O)(=O)OCc1cccc(-c2ccnc(Cl)n2)c1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: C[C@H]1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 64 %

Procedure:
Intermediate 125 Methanesulfonic acid 3-(2-chloro-pyrimidin-4-yl)-benzyl ester (0.70 g) and Intermediate 126 2-(S)-Methyl-piperazine-1-carboxylic acid tert-butyl ester (0.61 g) with diisopropylethylamine (0.70 mL) in ethylene glycol dimethyl ether (20 mL) was refluxed for 3 hours, cooled to room temperature, evaporated under reduced pressure and the residue was dissolved in dichloromethane, washed with water (3×), brine, dried over dried over Na2SO4, chromatographed on silica gel (dichloromethane:methanol=98:2) to give 0.60 g of oily product with yield 64%. LC-MS showed the product had the expected M+H+ of 403. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (s, 1H) 8.0 (s, 1H) 7.9 (d, 1H) 7.6 (d, 1H) 7.5 (m, 2H) 4.2 (S, 1 h) 3.8 (d, 1H) 3.4 (m, 2H) 3.0 (m, 1H) 2.7 (d, 1H), 2.6 (d, 1H) 2.1 (m, 2H) 1.5 (s, 9H) 1.2 (d, 3H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1.C(Br)(Br)(Br)[Br:49].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.O1CCCC1>[Br:49][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCO)c5)c4)cc23)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCBr)c5)c4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
A suspension of Intermediate 77 (0.65 g, 1.0 mmol) and carbon tetrabromide (1.0 g, 3.0 mmol) in dichloromethane (14 mL) was sonicated for 5 minutes and then cooled in an ice-water bath. Following the addition, via syringe, of a triphenylphosphine (0.52 g, 2.0 mmol) solution in tetrahydrofuran, the cooling bath was removed, allowing the mixture to stir overnight at room temperature. The mixture was quenched with ethanol and concentrated to foam under reduced pressure. The foam was taken up in tetrahydrofuran (15 mL) and treated as before with carbon tetrabromide (3.0 mmol) and triphenylphosphine (2.0 mmol). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The crude material was again taken up in tetrahydrofuran (15 mL) and treated as before with carbon tetrabromide (3.0 mmol) and triphenylphosphine (2.0 mmol). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The residue was taken up a suspension in acetone and filtered. The concentrated filtrate was purified via automated flash silica gel chromatography, using a 40 g Silicycle SiliSep flash column (hexanes/ethyl acetate). Concentration of the desired fractions under reduced pressure provided the title compound as straw-colored foam (0.35 g, 48%). ES/MS calcd. for C36H32BrN4O5S+ 711.1. Found m/z=711.2 (M+H)+.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C1(NC(C)(C)C)C=CC=CC=1.NC(N)=O.C(NN[CH2:25][C:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:37])=[C:32]([CH2:34][C:35]#[N:36])[CH:33]=1)=[O:27])(C)C>>[OH:37][C:31]1[CH:30]=[CH:29][C:28]([CH:26]([OH:27])[CH2:25][NH:4][CH:1]([CH3:3])[CH3:2])=[CH:33][C:32]=1[CH2:34][C:35]#[N:36]
Reactant: CC(C)N
Reactant: CC(C)NNCC(=O)c1ccc(O)c(CC#N)c1
Agent: CC(C)(C)Nc1ccccc1
Agent: NC(N)=O
Product: CC(C)NCC(O)c1ccc(O)c(CC#N)c1

Procedure:
The procedure of Example 1(c) is repeated with substitution of an equimolar amount of isopropylamine for phenyl-t-butylamine in that example. The resulting aminoketone, 5-[N-(isopropylamino)glycyl]-2-hydroxyphenylacetonitrile, is reduced according to the procedure of Example 1(d) to yield 2-hydroxy-5-[1-hydroxy-2-(isopropylamino)ethyl]-benzeneacetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2/[CH:12]=[C:13](\[F:16])/[CH:14]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>ClCCl>[CH2:20]([O:19][C:17](=[O:18])/[CH:22]=[CH:14]/[C:13](/[F:16])=[CH:12]\[C@@H:10]1[CH2:11][C@H:9]1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:21]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C/C(F)=C/[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)/C=C/C(F)=C\[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 91.6 %

Procedure:
The above aldehyde (0.5 g) was dissolved in dichloromethane (5 ml) under nitrogen and treated with carboethoxymethylenetriphenylphosphorane (0.67 g) at 25°. After 18 hours at 25° the solution was concentrated in vacuo and the residue washed with hexane. Combined hexane washings were concentrated in vacuo to give (±)-(2E,4E)-Ethyl-4-fluoro-5-[trans-2-(3,4-dichlorophenyl) cyclopropyl]penta-2,4-dienoate (0.58 g). NMR 1H: 7.30(1H,d), 7.00(3H,m), 6.05(1H,d), 5.90(1H,m), 4.20(2H,q), 2.00(2H,m), 1.30(3H,t), 1.30(2H,m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Cl)Cl.C[Si](C=[N+]=[N-])(C)C.CCOCC>CO>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:11]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-(t-butoxycarbonyl)azetidine-3-carboxylic acid (2.03 g, 10.09 mmol) was dissolved in MeOH (10 ml) and DCM (10 mL) and then cooled to 0° C. A 2M solution of trimethylsilyldiazomethane in ether (7.57 ml, 15.1 mmol) was then added drop-wise over 5 minutes. The solution was stirred for 10 minutes at 0° C. and then warmed to room temperature over 30 minutes. The solution was concentrated under reduced pressure to remove volatiles to afford crude 119, which was used directly in the next step without further purification. 1H NMR: 1.44 (s, 9H), 3.35 (m, 1H), 3.75 (s, 3H), 4.10 (d, 4H, J=7.6 Hz).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:9][CH:8]=1.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:9][CH:8]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: CNCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Product: CN(CCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1)Cc1ccccc1

Procedure:
In an analogous manner to that described in Example 44(e), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-methylamino-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 57(e)] with benzyl bromide there was obtained tert-butyl (3RS,4RS)-4-[4-[3-(benzyl-methyl-amino)-propoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 595 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][C:13]1([CH3:20])[NH:17][C:16](=[O:18])[NH:15][C:14]1=[O:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:12][C:13]1([CH3:20])[NH:17][C:16](=[O:18])[N:15]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[C:14]1=[O:19]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2C(=O)NC(C)(C)C2=O)ccc1[N+](=O)[O-]
Yield: 25 %

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (1.55 g, 10 mmoles), 5,5-dimethylhydantoin (1.28 g, 10 mmoles), K2CO3 (1.38 g, 10 mmoles) in DMF (15 ml) is introduced into a vial intended to be placed in a microwave oven and irradiated at 100° C. for 70 minutes, under magnetic stirring. The reaction mixture is then poured into water (200 ml) and extracted with AcOEt (2×75 ml). The organic phases are combined, washed with salt water, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on a silica column (eluent: Heptane/AcOEt:7/3). The expected compound is obtained in the form of a white solid with a yield of 25% (666 mg). Melting point: 177-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:22]1([CH:28]([N:35]=[C:36]=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH:28]([NH:35][C:36]([N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:14][CH2:13]1)=[O:37])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: CN1CCC(C(c2ccc(Cl)cc2)N2CCNCC2)CC1
Solvent: ClCCl
Product: CN1CCC(C(c2ccc(Cl)cc2)N2CCN(C(=O)NC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 1-((4-chlorophenyl)(1-methylpiperidin-4-yl)methyl)piperazine 0.1 g (0.325 mmol) dissolved in methylene chloride (20 ml) was added diphenylmethyl isocyanate 0.07 μg (0.325 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 0.14 g of desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])[CH:2]=1.C(C1C=NC=CC=1)(=O)C.[NH2:25][C:26]1[C:30]([C:31]#[N:32])=[CH:29][NH:28][N:27]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:27]3[N:28]=[CH:29][C:30]([C:31]#[N:32])=[C:26]3[N:25]=2)[CH:2]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccnc1
Reactant: N#Cc1c[nH]nc1N
Agent: CC(=O)c1cccnc1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3cccnc3)nc12
Yield: 15.6 %

Procedure:
Reaction of 1-pyridin-3-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0 mmol), prepared from commercially available 3-acetylpyridine according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (45 mg, 16%). MS (ISP) 290.2 [(M+H)+]; mp 193° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14](O)=[O:15])[CH2:9]2)=[N:4][N:5]([CH3:7])[CH:6]=1.B.C1COCC1>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([N:8]2[CH2:9][CH:10]([CH2:14][OH:15])[CH2:11][C:12]2=[O:13])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(N2CC(C(=O)O)CC2=O)n1
Agent: B
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(Br)c(N2CC(CO)CC2=O)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 17.3 %

Procedure:
To a solution of 1-(4-bromo-1-methyl-1H-pyrazol-3-yl)-5-oxopyrrolidine-3-carboxylic acid (511 mg) obtained in Step A of Example 7 in THF (3.0 mL) was added 1.1M borane-THF complex THF solution (5.0 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 20 hr, and diluted with ethyl acetate. The diluted solution was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and (methanol/ethyl acetate) to give the title compound (84 mg).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C:6]([CH3:11])([CH2:9][OH:10])[CH2:7][OH:8].[CH3:16][C:17]([CH3:21])([CH3:20])[CH:18]=O>C1C=CC=CC=1>[C:17]([CH:21]1[O:10][CH2:9][C:6]([O:5][CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])([CH3:11])[CH2:7][O:8]1)([CH3:20])([CH3:18])[CH3:16]
Reactant: CC(C)(C)C=O
Reactant: CC(CO)(CO)OCc1ccccc1F
Solvent: c1ccccc1
Product: CC1(OCc2ccccc2F)COC(C(C)(C)C)OC1

Procedure:
Using the procedure of Example 51, 2-(2-fluorobenzyloxy)-2-methyl-1,3-propanediol and 2,2-dimethylpropanal were reacted, using benzene as solvent, to give, after separation by column chromatography, r-2-(tert-butyl)-t-5-(2-fluorobenzyloxy)-5-methyl-1,3-dioxane, m.p. 50°-52°; and r-2-(tert-butyl)-C-5-(2-fluorobenzyloxy)-5-methyl-1,3-dioxane, m.p. 85°-87°. The ir and nmr spectra were consistent with the assigned structures.