Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.COC1C=CC(C[N:32]2[CH2:38][CH2:37][CH2:36][C:35]3[N:39]=[C:40]([CH2:42][O:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[S:41][C:34]=3[C:33]2=[O:50])=CC=1>O.C(#N)C>[O:43]([CH2:42][C:40]1[S:41][C:34]2[C:33](=[O:50])[NH:32][CH2:38][CH2:37][CH2:36][C:35]=2[N:39]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COc1ccc(CN2CCCc3nc(COc4ccccc4)sc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1NCCCc2nc(COc3ccccc3)sc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
A solution of ammonium cerium (IV) nitrate (1.08 g, 1.97 mmol) in H2O (1.5 mL) was added to a stirred solution of 5,6,7,8-tetrahydro-5-[(4-methoxyphenyl)methyl]-2-(phenoxymethyl)-4H-thiazolo[5,4-c]azepin-4-one (0.22 g, 0.56 mmol) in ACN (5 mL). The mixture was stirred at room temperature for 16 hours and then diluted with H2O and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield 5,6,7,8-tetrahydro-2-(phenoxymethyl)-4H-thiazolo[5,4-c]azepin-4-one (0.081 g, 52%) as a white solid. C14H14N2O2S LCMS: Rt 1.59, m/z 275 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nn1cccc1C(=O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nn1cccc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 143.4 %

Procedure:
1-Amino-2-(2-chlorobenzoyl)pyrrole (24.3 g, 0.12 mol) and t-butoxycarbonyl glycine (22.7 g, 0.13 mol) were dissolved in 300 ml of dichloromethane. Dicyclohexylcarbodiimide (26.8 g, 0.13 mol) was added over 3 minutes and the reaction mixture stirred at ambient temperature for 4 hours. The resultant slurry was filtered, and the the filtrate evaporated to give 65 g of oil. This oil was purified by flash chromatography (silica, 2:1 hexane-ethyl acetate) to give 21.9 g (48%) of cystals, m.p. 156°-158°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C[Li].[C:11](C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>C(OCC)C.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:11])[C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cnc(Cl)nc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2-chloro-5-methylpyrimidine (EXAMPLE 144, STEP 1) (0.50 g, 0.00389 mol) in diethyl ether (12 mL) at −30° C. and under nitrogen was added dropwise 1.4M methyllithium (2.90 mL, 0.00405 mol) and the reaction allowed to stir at −30° C. for 30 min and at 0° C. for 30 min. The reaction was quenched with a solution of acetic acid (0.242 mL), water (0.039 mL, and THF (0.8 mL) and then a solution of DDQ (0.92 g, 0.00405 mol) in THF was added. The reaction was stirred 5 min at rt, recooled to 0° C. and 3N sodium hydroxide added. The reaction was allowed to stir at 0° C. for 30 min after which a thick oily precipitate formed. The organic supernatant was decanted and the residue washed with diethyl ether (2×20 mL). The organic layers were dried over sodium sulfate, filtered through a pad of silica and the silica pad washed with diethyl ether. The filtrate was concentrated in vacuo to give the title compound as an oil. M.S.(M+1): 143.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:29])[CH2:26][O:27][CH3:28])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:32])[C:9]([C@@H:10]([CH3:30])[CH2:11]2)=[CH:8][C:7](=[O:31])[CH:6]=[CH:5]1.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:29])[CH2:26][O:27][CH3:28])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:32])[C:9](=[CH:8][C:7](=[O:31])[CH:6]=[CH:5]2)[C@@H:10]([CH3:30])[CH2:11]3)[CH2:14][CH2:15]1)(=[O:42])[CH3:41]
Reactant: COCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
In 4 ml of methylene chloride was dissolved 223 mg of 11β,21-dihydroxy-17α-methoxyacetoxy-6α-methyl-1,4-pregnadiene-3,20-dione obtained according to the method as described in Example 32. To this solution were added 404 mg of triethylamine and 204 mg of acetic anhydride, and the mixture was stirred for 5 hours at room temperature. The reaction mixture was then treated in the same manner as described in Example 7 whereby 186 mg (yield: 76.2%) of the title compound was obtained as colorless needle crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([CH3:32])[C:11]([NH:13][CH:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[NH:16][C:15]2=[O:31])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:39][O:40][C:41](=[O:44])[CH2:42]Br>CN(C=O)C>[CH3:39][O:40][C:41](=[O:44])[CH2:42][N:16]1[C:17]2[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:20][CH:14]([NH:13][C:11](=[O:12])[CH:10]([CH3:32])[CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:15]1=[O:31]
Reactant: C[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(NC(=O)C(C)Cc2ccc(Cl)c(Cl)c2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2S)-3-(3,4-dichlorophenyl)-2-methyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-1,4benzodiazepin-3-yl)propanamide (1.0 g) was dissolved in DMF and treated with cesium carbonate (2.1 g) and bromoacetic acid methyl ester (200□l), then left to stir at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water and the organic layer washed (water, brine), dried (magnesium sulphate) and evaporated in vacuo. Purification by flash silica chromatography afforded {3-[3-(3,4-Dichlorophenyl)-2-methyl-propionylamino]-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl}-acetic acid methyl ester.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:13]([O:15]CC)=O)#[N:2].Cl.C(OCC)(=O)C>[Pd].C(O)C>[C:13]1(=[O:15])[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:1][NH:2]1
Reactant: CCOC(=O)c1cc2ccccc2n1CC#N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1NCCn2c1cc1ccccc12
Reaction time: 6 h
Yield: 70.1 %

Procedure:
A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 3.47 g dry weight), 102a (8.00 g, 35.0 mmol), 12% hydrochloric acid (17.5 mL, 70 mmol), ethyl acetate (150 mL) and ethanol (100 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 6 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (10.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×50 mL), and the combined filtrates were concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (400 mL) and 10% aqueous potassium carbonate (300 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with ethanol (5 mL) to afford a 70% yield (4.57 g) of 102b as an off-white solid: mp 228-230° C.; 1H NMR (300 MHz, CDCl3) d 7.73 (d, 1H, J=8.1 Hz), 7.34 (m, 3H), 7.18 (m, 1H), 6.75 (br s, 1H), 4.29 (t, 2H, J=5.4 Hz), 3.84 (m, 2H); MS (ESI+) m/z 187.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1>O1CCOCC1.[Ni]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([Cl:11])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1cc(Cl)cnc1Cl
Reaction time: 22 h
Yield: 75.5 %

Procedure:
To a solution of 129.2 g (0.69 mol) of 2,5-dichloro-3-nitropyridine in 1300 ml of dioxane is added 26 0 g of Raney-nickel, that has previously been washed with ethanol. This mixture is then hydrogenated with hydrogen under normal pressure at 20-35° C. After uptake of 20% of the theoretical amount of hydrogen, another 30 g of washed Raney-nickel catalyst are added. After hydrogenating for 22 hours, the catalyst is filtered off, the solvent is evaporated and the residue is crystallized from hexane/ ethyl acetate. Thus, 84.9 g of 3-amino-2,5-dichloropyridine (78% of the theory) are obtained, which melts at 129-132° C.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.Cl.[NH2:11][OH:12].C(N(CC)CC)C>O1CCCC1>[OH:12][N:11]=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C=NO)cc1
Yield: 74 %

Procedure:
To a solution of 4-tolualdehyde (600 mg, 5 mmol) in tetrahydrofuran (3 ml) was added hydroxylamine hydrochloride (700 mg, 10 mmol) and triethylamine (1.4 ml, 10 mmol). The reaction was subjected to microwave; absorbance normal; temp: 150° C.; time; 600 (s). The solid material was filtered off, and solvent removed from the filtrate under reduced pressure. The residue was purified using column chromatography (2:1 Hexanes:Ethyl Acetate) to provide (hydroxyimino)(4-methylphenyl)methane (500 mg).
Reaction SMILES: [CH2:1]([O:8][C@:9]1([CH:37]=[CH2:38])[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@@H:10]1[O:32]S(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:8][C@:9]1([CH:37]=[CH2:38])[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@H:10]1[OH:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OS(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C[C@]1(OCc2ccccc2)[C@H](O)[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1COCc1ccccc1
Yield: 74.4 %

Procedure:
A solution of nucleoside 25 (2.53 g, 4.66 mmol) in a mixture of ethanol (50 cm3), water (50 cm3) and 1 M aqueous sodium hydroxide (15 cm3) was stirred under reflux for 16 h. The mixture was neutralised using dilute aqueous hydrochloric acid, the solvent was evaporated under reduced pressure, and the residue was extracted with dichloromethane (3×120 cm3). The combined extract was washed with saturated aqueous sodium hydrogencarbonate (3×150 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1) as eluent to give 26 as a white foam (1.61 g, 74%). δH (CDCl3) 9.89 (1H, br s, NH), 7.50 (1H, d, J 1.1, 6-H), 7.41-7.26 (Bn), 6.28 (1H, d, J 2.8, 1′-H), 6.05 (1H, dd, J 11.1, 17.9, 1″-H), 5.58-5.50 (2H, m, 2″-Ha, 2″-Hb), 4.98 (1H, d, J 9.0, 2′-OH), 4.64-4.31 (6H, m, 2′-H, 4′-H, Bn), 3.73 (2H, m, 5′-Ha, 5′-Hb), 1.73 (1H, d, J 0.6, CH3). δC (CDCl3) 165.1 (C-4), 150.5 (C-2), 138.4, 138.0, 136.7 (C-6, Bn), 130.4 (C-1″), 128.8, 128.6, 128.5, 128.1, 128.0, 127.8 (Bn), 120.6 (C-2″), 108.1 (C-5), 88.6 (C-1′), 87.9 (C-3′), 87.2 (C-4′), 73.7 (C-2′), 71.8 (C-5′), 69.7, 66.3 (Bn), 12.3 (CH3). Found: C, 66.8; H, 6.2; N, 5.9; C26H28N2O6 requires C, 67.2; H, 6.1; N, 6.0.
Reaction SMILES: Br[CH2:2][C:3](=[N:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])[O:4][CH2:5][CH3:6].[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[N:23]([CH2:2][C:3](=[N:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])[O:4][CH2:5][CH3:6])=[N+:24]=[N-:25]
Reactant: CCOC(CBr)=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CN=[N+]=[N-])=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 80 °C

Procedure:
to a solution of 3.8 parts of 2-(2-bromo-1-ethoxyethylideneamino)-5-chlorobenzophenone produced in Step (1) in 30 parts by volume of dimethylformamide is added 0.72 part of sodium azide. The mixture is heated at 80° C. for 10 minutes, and is poured into 60 parts by volume of ice water. The resulting oily precipitate is extracted with ethyl acetate. Ethyl acetate layer is washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent, 2-(2-azido-1-ethoxyethylideneamino)-5-chlorobenzophenone is obtained quantitatively as an oily substance. The product shows an absorption band at 2100 cm-1 due to N3 in an infrared absorption spectrum.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[O:29]=[S:30]1(=[O:36])[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[O:29]=[S:30]1(=[O:36])[CH2:34][CH2:33][CH:32]([NH:35][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:31]1
Reactant: NC1CCS(=O)(=O)C1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCS(=O)(=O)C3)ccc21
Yield: 73.9 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-amide (39 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 1,1-dioxo-tetrahydro-1λ6-thiophen-3-ylamine (30 mg), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 527; and 1H NMR (DMSO-d6, 400 MHz): δ 8.72 (br, 1H), 8.09 (d, 1H), 7.92 (d, 1H), 7.78-7.63 (m, 2H), 7.48 (d, 1H), 7.34 (d, 1H), 4.72 (m, 1H), 3.62 (s, 3H), 3.52 (m, 1H), 3.38 (m, 1H), 3.20 (m, 1H), 3.08 (m, 1H), 2.43 (t, 2H), and 2.25 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][NH2:24])[CH:19]=[CH:20][CH:21]=1>>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:24][CH2:23][CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:25])[F:26])[CH:17]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: NCCc1cccc(C(F)(F)F)c1
Product: FC(F)(F)Oc1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1

Procedure:
(4-trifluoromethoxy-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine was synthesized in analogy to the above procedure using 1.232 g 4-(trifluoromethoxy)benzaldehyde (6.48 mmol) and 0.817 g 2-(3-trifluoromethyl-phenyl)-ethylamine (4.32 mmol), 1.31 g (83%) of a light yellow liquid were obtained. MS: 364 (M+H)+.
Reaction SMILES: Br[CH:2]([CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][NH2:28]>C(#N)C>[C:6]([O:5][C:3](=[O:4])[CH:2]([CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[NH:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][NH2:28])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)C(Br)COCc1ccc([N+](=O)[O-])cc1
Reactant: NCCNCCN
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(COCc1ccc([N+](=O)[O-])cc1)NCCNCCN
Temperature: 35 °C
Yield: 79.8 %

Procedure:
A solution of 14 g of t-butyl 2-bromo-3-[(4-nitrophenyl)methoxy]propanoate (prepared according to the procedure described by P. L. Rings et al., Synth. Commun., 1993, 23, 2639) (0.0389 mol), in 30 ml of acetonitrile was added to a solution of 20 g of diethylenetriamine (0.19 mol) in 20 ml of acetonitrile kept at 0°-5° C. and under inert atmosphere. The solution was then heated to 35° C. for 4 h. The solvent was evaporated under vacuum and 100 ml of a NaCl saturated solution were added to the residue. The solution was extracted with Et2O; the organic phase was washed with H2O, dried and concentrated under vacuum to obtain 12 g of the desired product (0.031 mol).
Reaction SMILES: [CH3:1][C@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[H][H].C(OC(C)C)(C)C>[C].[Pd].C(O)(=O)C>[CH3:1][C@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: C[C@@H](COc1ccncc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Product: C[C@@H](COC1CCNCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 107.1 %

Procedure:
tert-Butyl [(1S)-1-methyl-2-(pyridin-4-yloxy)ethyl]carbamate (30 g), acetic acid (300 mL) and 10% palladium-carbon (7.5 g) were charged into pressure-resistant reactor vessel, and the mixture was stirred at 80° C. for 6 hr at 0.8 MPa hydrogen pressure. The mixture was allowed to cool to room temperature, and the pressure was reduced to normal level. The insoluble material was removed by filtration, and the filtrate was concentrated. Ethyl acetate (300 mL) was added to the residue, and the mixture was extracted with 10% aqueous citric acid solution (300 mL). The ethyl acetate layer was extracted again with 10% aqueous citric acid solution (150 mL). The aqueous layers were combined, adjusted to pH 12 with 8M aqueous sodium hydroxide solution, and extracted twice with toluene (300 mL). The toluene layers were combined and concentrated. Methanol (30 mL), ethyl acetate (120 mL) and succinic acid (12.1 g) were added to the residue and the mixture was stirred to give crystals. After stirring for 1 hr, diisopropyl ether (150 mL) was added, and the mixture was stirred for 1 hr. The resulting crystals were collected by filtration, washed with diisopropyl ether (150 mL) and dried to give the title compound (32.9 g) as white crystals.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:17][NH2:18]>CCO>[CH3:17][NH:18][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN
Reactant: CCOC(=O)c1cc2cccnc2nc1Cl
Solvent: CCO
Product: CCOC(=O)c1cc2cccnc2nc1NC
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
Ethyl 2-chloro-1,8-naphthyridine-3-carboxylate (100 mg, 0.42 eq.) was dissolved in EtOH. MeNH2 (71.8 μl, 11.84 M aqueous solution) was added to the solution. The mixture was stirred at r.t. for 18 h. The solvents were removed under reduced pressure. The residue was dissolved in EtOAc and washed with water (×2). The organic extract was dried (MgSO4), filtered and concentrated to yield 60.2 mg (62%) of the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:26]1([C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:12][CH2:11][C:7]2[N:6]=[C:5]([CH2:4][NH2:1])[CH:10]=[CH:9][CH:8]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: [N-]=[N+]=NCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
A solution of 2-(azidomethyl)-6-(triphenylmethoxymethyl)pyridine (2.78 g, 6.8 mmol) in THF (25 mL) was treated with triphenylphosphine (1.96 g, 7.5 mmol), stirred at room temperature for 3 h, treated with water (184 μl, 10.2 mmol), stirred at room temperature for a further 7 days and concentrated in vacuo. The resulting oil was purified by chromatography [SiO2; EtOAc:MeOH:NH3 (1:0:0) to (9:1:0.2)] to give the title compound (2.33 g, 90%) as a yellow oil; NMR δH (400 MHz, CDCl3) 1.74 (2H, s), 3.90 (2H, s), 4.34 (2H, s), 7.14-7.33 (10H, m), 7.50-7.52 (6H, m) and 7.65-7.74 (2H, m); M/Z 381 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:3]([O:8][CH:7]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:2][CH2:9][CH3:6]
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCOC(OCCCC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 192 %

Procedure:
Heat a solution of 5-fluoro-2-nitro-benzaldehyde (10 g, 59.17 mmol), butanol (20 mL, 219 mmol) and p-toluenesulfonic acid (600 mg, 3.15 mmol) in toluene (200 mL) at reflux for 2 hours in a flask equipped with a Dean-Stark trap. Cool the reaction mixture to room temperature, dilute with ethyl acetate (400 mL), and wash sequentially with saturated aqueous sodium bicarbonate (300 mL×3) and saturated aqueous sodium chloride (300 mL×2). Dry the organic phase over sodium sulfate and concentrate under reduced pressure to provide the desired compound as a pale yellow oil (17 g, 96%).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:17]([O:16][C:14]([CH2:13][O:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])=[O:15])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1c(C=O)cccc1OC

Procedure:
A solution of 2-hydroxy-3-methoxybenzaldehyde (6.08 g), ethyl bromoacetate (4.9 ml) and potassium carbonate (12.14 g) in N,N-dimethylformamide (30 ml) was stirred for 2 hours at ambient temperature. Water was added to the reaction mixture, and the resulting precipitates were collected by filtration and recrystallized with ethanol to give 2-ethoxycarbonylmethoxy-3-methoxybenzaldehyde (5.04 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.N[N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CN1CCN(N)CC1
Solvent: CCO
Product: CN1CCN(Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.4 %

Procedure:
A mixture of 35 g of 4-chloro-1,2-dinitrobenzene and 20 g of 1-amino-4-methylpiperazine in 200 ml of 96° EtOH is stirred for 24 hours at RT. The reaction mixture is evaporated under vacuum and the residue is chromatographed on silica using a DCM/AcOEt mixture (80/20; v/v) as the eluent to give 17.5 g of the expected product after crystallization from an iso ether/heptane mixture (50/50; v/v). M.p.=108° C.