Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([C@@H:30]([CH3:49])[C@H:31]([N:46]=[N+:47]=[N-:48])[C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:46]([C@H:31]([C:32]1[CH:33]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[C@@H:30]([NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[CH3:49])=[N+:47]=[N-:48]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OC(C)(C)C)[C@@H](C)[C@H](N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@H](N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl{(1S,2R)-2-azido-2-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (21.7 mg, 0.030 mmol) in CH2Cl2 (2 mL) was added TFA (200 μL). The reaction was stirred at room temperature for 1 hour and then diluted with CH2Cl2 (25 mL). The CH2Cl2 solution was washed with 1 N NaOH (15 mL) and the aqueous phase was re-extracted with CH2Cl2 (25 mL). The organic extracts were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 15% EtOAc/hexanes afforded (1R,2S)-1-azido-1-[3,5-bis(trifluoromethyl)phenyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)bi phenyl-2-yl]methyl}propan-2-amine. Rf=0.45 (15% EtOAc/hexanes). LCMS=619.2 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:19]1([C:22]2[C:27]([C:28](O)=[O:29])=[CH:26][N:25]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)[N:23]=2)[CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][C:28]([C:27]2[C:22]([CH:19]3[CH2:21][CH2:20]3)=[N:23][C:24]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=3)=[N:25][CH:26]=2)=[O:29])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[4-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 84A]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[4-(2-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: C([O:8][C:9]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:10]=1[NH2:11])C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[NH2:11][C:10]1[CH:12]=[CH:13][C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:15][C:9]=1[OH:8]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OCc3ccccc3)c2)cn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(O)c2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
To a solution of 2-(benzyloxy)-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}aniline (26 g) in a mixture of tetrahydrofuran (200 mL) and methanol (50 mL) was added palladium on carbon (5 g, 10 wt %, wet), and the mixture was stirred at room temperature for 5 h under hydrogen atmosphere. The mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure. The residual oil was solidified with diethyl ether, and the solid was washed with ethyl acetate-diethyl ether to give the title compound (17.28 g, 88%) as a grayish solid. MS 281 (MH+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=O)=[CH:5][CH:4]=1.[CH2:14]([SH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>C1(C)C=CC=CC=1>[CH2:14]([S:21][C:7](=[S:23])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: SCc1ccccc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(C(=S)SCc2ccccc2)cc1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of 4-trifluoromethylbenzoic acid (1.90 g), benzyl mercaptan (1.24 g) and phosphorus pentasulfide (4.44 g) in toluene (40 ml) was refluxed for 10 h. A dark red color was developed immediately after heating. After the reaction was complete (as monitored by GC-MS), it was cooled to room temperature and purified by a column chromatography packed with neutral alumina, eluting with benzene. Removal of the solvent by distillation gave the single compound, benzyl-4-trifluoromethyidithiobenzoate (2.30 g, 74%). It was further characterized by 1H and 13C-NMR.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([NH2:13])[CH2:5][CH2:4]1.[O-:14][C:15]#[N:16].[K+]>O>[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([NH:13][C:15]([NH2:16])=[O:14])[CH2:5][CH2:4]1
Reactant: NC1CCC(=O)c2ccccc21
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC1CCC(=O)c2ccccc21
Reaction time: 72 h

Procedure:
A sample of 26.55 g. of 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine hydrochloride is dissolved in 250 ml. water and a solution of 21.8 g. of potassium cyanate in 75 ml. of water added. The reaction mixture is stirred for 72 hours, the precipitate formed in the reaction is collected by filtration and dried to afford 21.45 g. of the title compound, m.p. 225° C. (dec.).
Reaction SMILES: [H-].[Na+].I[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[CH3:11][C:12]1([CH3:37])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH:20]=2)[N:15]=[C:14]([S:35][CH3:36])[CH2:13]1>C1COCC1>[CH3:37][C:12]1([CH3:11])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH:20]=2)[N:15]=[C:14]([S:35][CH2:36][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:13]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(SC)=N3)cc1
Reactant: CCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCSC1=Nc2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2C(C)(C)C1

Procedure:
0.025 g (0.694 mmol) of sodium hydride in 2 ml of THF, 0.229 g (0.631 mmol) of ethyl 4-[(4,4-dimethyl-2-thio-1,2,3,4-tetrahydro-6-quinolinyl)ethynyl]benzoate (Compound 8) in 2 ml of THF and 1.03 ml (6.31 mmol) of iodoheptane were reacted substantially in accordance with the procedure used for the preparation of ethyl 4-[(4,4-dimethyl-2-methylthio-3,4-dihydro-6-quinolinyl)ethynyl]benzoate (Compound 9). Purification by flash chromatography (silica gel, 10% ethyl acetate in hexane) yielded the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1)=[N:13][C@H:12]1[C@@H:7]2[CH2:8][O:9][CH2:10][CH2:11]1)[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>ClCCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[O:26])=[CH:27][CH:28]=1)=[N:13][C@H:12]1[C@@H:7]2[CH2:8][O:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCOC[C@H]21
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCOCC3)cc1)=N[C@@H]1CCOC[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1 mmol of 4-((4aR,10aR)-6-Ethoxy-7-methoxy-1,4,4a,10a-tetrahydro-2H-3-oxa-10-aza-phenanthren-9-yl)-benzoic acid, 5 mmol of triethyl amine and 1.1 mmol of O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (HBTU) in 20 ml of dichloromethane is stirred for 30 min at RT. After addition of 1.1 mmol of morpholine the suspension is stirred for 60 min at RT. The mixture is concentrated under reduced pressure and the solid residue is purified by column chromatography on SiO2 (n-hexane/ethyl acetate/triethylamine 4/5/1 vol/vol/vol), the main product fraction is separated and concentrated yielding the title compound as grayish solid foam. M.p. 116-120° C. (unsharp, enamel-like shrinking starting at about 61° C.)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH3:9])[N:5]=[C:4]([CH2:20][NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CC#N.C(O)(C(F)(F)F)=O>O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][N:8]([CH3:9])[C:6]2[N:7]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[N:3]=[C:4]([CH2:20][NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: CN(CCCc1ccc(F)cc1)c1nc(Cl)nc(CNCCc2ccc(O)cc2)n1
Reactant: CN1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CN1CCN(c2nc(CNCCc3ccc(O)cc3)nc(N(C)CCCc3ccc(F)cc3)n2)CC1
Yield: 97 %

Procedure:
The title compound was prepared in 97% yield via the procedure outlined for Example 14 using 4-{2-[(4-chloro-6-{[3-(4-fluorophenyl)propyl]methylamino}-1,3,5-triazin-2-yl)methylamino]ethyl}phenol and 1-methypiperazine to give a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.12 (s, br, 2H), 7.06 (d, 2H, J=8.0), 6.94 (m, 2H); 6.72 (d, 2H, J=8.0), 4.88 (s, br, 1H) 3.79-3.58 (m, 9H), 3.08 (s, 3H), 3.02 (s, br, 3H), 2.78 (m, 2H), 2.60 (t, 2H, J=7.0), 2.45 (s, br, 4H), 2.34 (s, 3H), 1.88 (m, 2H); low-resolution MS (ES+) m/e 495 (MH+); RP-HPLC (Capcell Pak C-18 25 cm×4.6 mm; 0-95% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=12.04 min, 99% purity.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][OH:18])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22].N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]#[C:16][CH2:17][O:18][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:13][CH2:14]1)=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCO)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 520 mg (1.95 mmol) of trans-[4-(3-Hydroxy-prop-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 14 ml CH2Cl2 was treated at 0° C. with 0.17 ml (2.14 mmol) methanesulfonylchloride, 0.235 ml (2.92 mmol) pyridine and 238 mg (1.95 mmol) DMAP. The reaction mixture was warmed up over night to room temperature, water (2 ml) was added and the reaction was stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×) the organic phases were washed with aqueous saturated NaHCO3 (2×), aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 435 mg (65%) of trans-Methanesulfonic acid 3-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl]-prop-2-ynyl ester, MS: 345 (M).
Reaction SMILES: [H-].[Na+].[CH2:3](P(=O)(OCC)OCC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O)([O-:20])=[O:19].Cl>CN(C)C=O>[N+:18]([C:21]1[CH:22]=[C:23](/[CH:24]=[CH:3]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:26]=[CH:27][CH:28]=1)([O-:20])=[O:19]
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(/C=C/c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 1.48 g) in N,N-dimethylformamide (40 ml) was added a solution of diethyl benzylphosphonate (7.69 g) in N,N-dimethylformamide (40 ml) at 0° C. The mixture was stirred at room temperature for 30 minutes, then a solution of 3-nitrobenzaldehyde (5.09 g) was added thereto. After stirring at 50° C. for 1 hour, the mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate 3 times. The combined organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give (E)-3-nitrostilbene (3.97 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[CH2:21]1[CH2:25]OC[CH2:22]1.Cl[CH:27]1[N:32](C)[C:31]([Cl:34])=CC=[N:28]1>O>[Cl:34][C:31]1[N:32]=[CH:27][N:28]=[C:25]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[C:21]=1[CH3:22]
Reactant: CN1C(Cl)=CC=NC1Cl
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 95 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (2.47 g, 12.3 mmol) and potassium tert-butoxide (1.42 g, 12.7 mmol) were added to a THF (20 mL) solution of 2,4-dichloro-3-methylpyrimidine (1.60 g, 9.82 mmol), and the mixture was stirred for 2 hours. To the reaction solution, water was added, followed by extraction with ethyl acetate three times. The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-60:40, V/V) to obtain the title compound as colorless oil (3.07 g, yield: 95%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Si:12]([O:29][CH2:30][CH2:31]Br)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Si:12]([O:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)([C:25]([CH3:26])([CH3:27])[CH3:28])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1

Procedure:
A mixture of methyl 4-hydroxybenzoate (3.25 g, 22.0 mmol, 2-(tert-butyldiphenylsilyloxy) ethyl bromide (8.0 g, 22.0 mmol, powdered anhydrous potassium carbonate (12 g) and potassium iodide (0.1 g) in acetone (250 ml) was heated under reflux for 48 h. The solid was then filtered and the filtrate was evaporated under reduced pressure.
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].C[O-].[Na+].[C:13]1([C:23](OC)=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.Cl>O.CO>[C:13]1([C:23]2[NH:5][N:6]=[C:7]([NH2:9])[N:8]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: N=C(N)NN
Reactant: COC(=O)c1cccc2ccccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CO
Product: Nc1n[nH]c(-c2cccc3ccccc23)n1
Temperature: 0 °C
Reaction time: 22 h
Yield: 52.3 %

Procedure:
To a stirred mixture of N-aminoguanidine nitrate (2.74 g, 20 mmol) and anhydrous methanol (25 mL) cooled to 0° C. was added sodium methoxide solution (25% in methanol, 4.57 mL, 20 mmol) dropwise. The resulting mixture was stirred at 0° C. for 10 min before methyl 1-naphthoate (0.93 g, 5 mmol) was added. The mixture was then stirred at 0° C. for 10 min, RT for 10 min, 70° C. for 22 hr, and 75° C. for 19 hr. The reaction mixture was cooled and diluted with 10 mL of water. Concentration under vacuum gave a slightly cloudy solution which was acidified to pH=3-4 with 3 N aqueous HCl solution. The solid obtained was filtered, washed with water, and triturated with ethanol to give 0.55 g (52% yield) of 5-(naphthalen-1-yl)-1H-1,2,4-triazol-3-amine as a yellow solid. (M+H)+=211.16.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(P(N(C)C)(N(C)C)=O)C>[C:24]1([CH2:23][CH2:22][CH2:21][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)[CH2:2][CH2:3]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(CCN2CCN(CCCc3ccccc3)CC2)cc1
Temperature: 55 °C
Yield: 76 %

Procedure:
A mixture of 40 ml. HMPT, 23.6 g. (90 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate and 8.96 g. (45 mmole) 3-bromopropylbenzene is maintained at 110° C. for 22 hours, whereby, immediately after mixing together, the temperature increases to about 55° C. and the formation of a pale precipitate is observed. At 110° C., a clear, red-brown solution is present, from which, upon cooling, a product crystallises out. It is poured into a little water, extracted with diethyl ether, the ether phase is washed with water, dried with anhydrous sodium sulphate and evaporated. The crude product is dissolved in diethyl ether and converted into the dihydrochloride by means of hydrogen chloride-containing diethyl ether and recrystallised from ethanol containing 2 drops of concentrated hydrochloric acid; m.p. 273° C. (decomp.). Yield 76% of theory.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][C:11]([F:21])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[C:16]([CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:21])[CH:12]=2)[N:7]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[C:6]=1[C:4]([OH:3])=[O:5])([OH:18])=[O:17]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)[nH]c2ccc(F)cc12
Reactant: BrCc1cccc2ccccc12
Product: O=C(O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
Using general procedure B, 3-ethoxycarbonylmethyl-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (Lit. 10) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 376.4 ([M−H]−).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1.[OH-].[Na+]>>[C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1cc(Nc2cccc(-c3ccccc3)c2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-aminobiphenyl (65 mg, 0.386 mmol) similar to Example 58. The mixture was basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was collected by filtration, washed with excess water:ethanol (1:1) and isolated as a light brown solid (64 mg, 85%). 1H NMR (CDCl3): 9.67 (s, 1H), 8.75 (d, J=5.4 Hz, 2H), 7.68 (s, 1H), 7.63–7.37 (m, 10H), 6.98 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)([C:14]([O:16]CC2C=CC=CC=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14](=[O:16])[NH:41][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:30]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NC1CCCCC1
Reactant: COC(=O)c1ccc(CC2(C(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC2(C(=O)NC3CCCCC3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of solution of 4-(4-methoxycarbonyl-benzyl)-piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (9.35 mmol; 3.53 g) in DMF (40 mL) was added cyclohexylamine (11.22 mmol; 1.28 mL), N, N-diisopropyl-N-ethylamine (23.38 mmol; 4.14 mL) and HBTU (11.22 mmol; 4.26 g), and the resulting mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, and the resulting solution was washed with a 1N hydrochloric acid solution (2×25 mL), and brine (25 mL), and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 70% EtOAc in heptane) to yield 4-cyclohexylcarbamoyl-4-(4-methoxycarbonyl-benzyl)-piperidine-1-carboxylic acid tert-butyl ester after evaporation. The material thus obtained was dissolved in dichloromethane (25 mL) and trifluoroacetic acid (25 mL) was added. The resulting mixture was stirred for 2 hours at room temperature and evaporated. The residue was dissolved in dichloromethane (300 mL) and washed with a saturated sodium bicarbonate solution (50 mL) and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated to yield 4-(4-cyclohexylcarbamoyl-piperidin-4-ylmethyl)-benzoic acid methyl ester. MS (ESI) m/z 459.30 [M+H]+.
Reaction SMILES: [Cl-:1].[Ce+3].[Cl-].[Cl-].[I-].[Na+].Br[CH2:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:10].[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[ClH:1].[CH2:20]([N:27]1[CH2:32][CH2:31][C:30]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH2:15][CH2:14]3)=[O:10])([OH:33])[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [Cl-]
Reactant: O=C(CBr)c1ccc2c(c1)CCN2
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Ce+3]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: O=C(CC1(O)CCN(Cc2ccccc2)CC1)c1ccc2c(c1)CCN2
Reaction time: 2 h
Yield: 41.4 %

Procedure:
Anhydrous cerium chloride (0.99 g, 4.0 mmol) and sodium iodide (1.8 g, 12.0 mmol) are added to 10 ml of anhydrous tetrahydrofuran as a solvent to form a suspension. Dissolving 0.96 g (4.0 mmol) of 2-bromo-1-(5-indolinyl)-ethanone and 0.76 g (4.0 mmol) of N-benzyl-4-piperidone into 10 ml of anhydrous tetrahydrofuran, and the solution is added dropwise to the above suspension and reacting at room temperature for 2 hours. Operating according to the post-treatment procedure in General Method three to obtain 0.64 g of a white crystal, with yield of 36.2%.