Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCOC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCOC3)c2n1
Yield: 66.5 %

Procedure:
A solution of 2-butyloxy-8-methoxy-9-[2-(tetrahydro-3-furanyl)ethyl]-9H-purin-6-amine (102 mg) in methanol (1 mL) was treated with 4N HCl in 1,4-dioxane (0.5 mL) for 1.5 h. The reaction was evaporated and the residue treated with water then basified with saturated sodium bicarbonate solution. The resulting solid was filtered, washed with water and dried to give the title compound (65 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]([O:26]C)=[O:25])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH3:23])=[CH:17][N:16]=2)=[N:11][CH:10]=1.[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH3:23])=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: COCc1ccc(Nc2ncc(Sc3ccnc(C(=O)OC)c3F)s2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCc1ccc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)nc1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
Methyl 3-fluoro-4-(2-(5-(methoxymethyl)pyridin-2-ylamino)thiazol-5-ylthio)picolinate (0.061 g, 0.150 mmol) was dissolved in THF (5 mL) and treated aq. NaOH (5N, 0.195 mL, 0.975 mmol). The reaction was stirred at 23° C. for 30 minutes, then water (1 mL) was added and the reaction was stirred for 30 more minutes. The reaction was then acidified with conc. HCl to pH ˜2 and water was added again. This was extracted with ethyl acetate/THF and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (0.035 g, 59%) as a solid which was used as such for the next reaction. HPLC ret. time (Condition B): 1.120 min. LC/MS (M+H)+: 393.
Reaction SMILES: O[C:2]1[C:3]2[S:10][C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:2]1[C:3]2[S:10][C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc(C)cc(-c2cc3ncnc(O)c3s2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(-c2cc3ncnc(Cl)c3s2)c1
Temperature: 100 °C

Procedure:
The hydroxy compound prepared in Step 1 was treated with phosphorous oxychloride (150 mL) and diisopropylethylamine (2 mL). The mixture was then heated at 100° C. for 4 hours. The solvents were evaporated under reduced pressure and the residue was carefully treated with ice water. The resulting solid was filtered off and crystallized from ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:29]([N+:30]([O-])=O)=[CH:28][CH:27]=[CH:26][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:14][CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10]>C(O)C.[Pd]>[NH2:1][C:2]1[C:29]([NH2:30])=[CH:28][CH:27]=[CH:26][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:14][CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:8](=[O:13])[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1c(OCCN(CCCc2c[nH]c3ccccc23)C(=O)C(F)(F)F)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(OCCN(CCCc2c[nH]c3ccccc23)C(=O)C(F)(F)F)c1N
Reaction time: 6 h
Yield: 77.7 %

Procedure:
To a solution containing N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-[3-(1H-indol-3-yl)-propyl]-acetamide (3.86 g, 8.57 mmol) in ethanol (40 ml) under nitrogen was added 10% palladium on carbon (1 g). The mixture was hydrogenated at 40 psi for 6 hours. The catalyst was filtered, washed with ethanol and the filtrate was concentrated to give the crude product. Purification by chromatography (40% ethyl acetate-hexanes) afforded 2.8 g (78.8%) of product as a viscous brown oil; MS EI m/e 420 (M+).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([NH:20][C:21]([C@@H:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)=[O:22])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([NH:20][C:21]([C@@H:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH2:25][NH:24]2)=[O:22])[CH2:16][CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)[C@H]1C(=O)NN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NN1CCN(C(c2ccccc2)c2ccccc2)CC1)[C@H]1NCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(tert-Butoxycarbonyl)-3-phenyl-[(2S)-2-pyrrolidinecarboxylic acid] (4-benzhydrylpiperazine-1-yl) amide (15) (2.70 g; 5.14 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 2 hours at ambient temperature. The reaction mixture is cooled in an ice-bath and the pH adjusted to 9 with saturated potassium carbonate solution. The mixture is poured onto water (30 mL) and extracted with methylene chloride (1×60 mL, 2×20 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product. CIMS: MH+ 426
Reaction SMILES: [C:1]([C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[NH:8][C:9]([SH:11])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl.[CH3:18][O:19][C:20]1[C:21]([CH2:28]Cl)=[N:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>O.C(O)C>[C:1]([C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[NH:8][C:9]([S:11][CH2:28][C:21]3[C:20]([O:19][CH3:18])=[C:25]([O:26][CH3:27])[CH:24]=[CH:23][N:22]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2nc(S)[nH]c2cc1C
Reactant: COc1ccnc(CCl)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccnc(CSc2nc3cc(C(C)=O)c(C)cc3[nH]2)c1OC
Reaction time: 6 h
Yield: 61.7 %

Procedure:
5-Acetyl-6-methyl-2-mercapto-1H-benzimidazole (4.2 g, 20 mmol) and NaOH (0.8 g, 20 mmol) in H2O (1 ml) were dissolved in 60 ml ethanol. 3,4-dimethoxy-2-chloromethylpyridine hydrochloride (≈17 mmol) as a crude material was added and the mixture was heated to boiling. NaOH (0.7 g, 17 mmol) in H2O (1 ml) was added and the reflux was continued for 6 hours. The solvent was evaporated off and the residue was diluted with methylene chloride and water. The organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure. Crystallizing from acetonitrile gave the title compound, (3.75 g, 62%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:39][NH:40][O:41][CH3:42].C(N(CC)CC)C>C(Cl)Cl>[CH3:42][O:41][N:40]([CH3:39])[C:13]([C@@H:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9]1)=[O:15]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C

Procedure:
In a 500 mL round-bottomed flask under a positive pressure of nitrogen, was added a methylene chloride (125 mL) solution of (R)—N-Boc-pyrroldine-3-carboxylic acid (7.00 g, 0.0325 mol). This solution was cooled to 0° C. using an ice/water bath and treated sequentially with, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.48 g, 0.0390 mol) and 1-hydroxybenzotriazole (5.29 g, 0.0391 mol) in single portions. Following the addition of the coupling agents, the reaction mixture became cloudy, but upon further stirring a clear solution was obtained. The reaction mixture was stirred at 0° C. for 20 min then charged with N,O-dimethylhydroxylamine hydrochloride (4.78 g, 0.0490 mol) and triethylamine (13.5 mL, 0.0968 mol). The cooling bath was removed and the reaction mixture was allowed to warm to room temperature with stirring over a period of 1 h. The resulting solution was diluted with dichloromethane (600 mL) and 1 N HCl (1000 mL), mixed thoroughly and separated. The organic layer was washed with saturated aqueous sodium bicarbonate (300 mL) and saturated aqueous sodium chloride (300 mL), then dried over Na2SO4, filtered and concentrated to give tert-butyl (3R)-3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate as a colorless oil (7.00 g; 83%). 1H NMR (400 MHz, CDCl3) δ 3.73 (s, 3H), 3.60-3.37 (m, 4H), 3.21 (s, 3H), 2.35-2.09 (m, 3H) 1.47 (s, 9H); ESI MS found for C12H22N2O4 m/z [159.1 (M+1-Boc)]
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH2:9]([N:27]=[C:28]=[O:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:9]([NH:27][C:28]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH2:8])=[O:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: NCCCCCCN
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCCCCCN

Procedure:
29 grams 1,6-hexanediamine (0.25 mole) was reacted with 20 gms (0.068 mole) octadecyl isocyanate as in Example 2. Yield: 25.5 gms, melting point 123°-168°C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1)([CH3:12])[CH3:11]
Reactant: COc1cccc(I)c1
Reactant: CC(C)c1ccccc1S
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1cccc(Sc2ccccc2C(C)C)c1
Yield: 93.3 %

Procedure:
The general procedure in example 39 was followed. 3-Iodoanisole (234 mg, 1.0 mmol), 2-Isopropylbenzenethiol (90% purity, 168 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-(2-isopropylphenyl)sulfanylanisole (241 mg, 93% yield) as colorless liquid. Column chromatographic solvent (hexane/ethyl acetate=40/1). Rf=0.3 (hexane/ethyl acetate=40/1). 1H NMR (CDCl3, 300 MHz) δ 7.29-7.36 (m, 3 H), 7.09-7.17 (m, 2 H), 6.67-6.73 (m, 3 H), 3.72 (s, 3 H), 3.54 (hept, 1 H, J=6.9 Hz), 1.22 (s, 3 H), 1.19 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 160.1, 150.9, 139.0, 134.5, 132.1, 129.9, 128.9, 126.8, 126.3, 121.4, 114.4, 111.9, 55.6, 31.1, 24.0. IR (neat, cm−1) 3060, 2962, 2867, 2834, 2362, 2343. MS (EI) m/z (relative intensity) 258 (100), 241 (30), 225 (30). HRMS (EI), Cald. for C16H18OS 258.1078. Found 258.1080.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:8]=[C:7]([Br:15])[C:6]=1[OH:16])[CH3:2].[CH:18](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[N:8]=[C:7]([Br:15])[C:6]=1[O:16][CH3:18])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1cc(C(C)(C)C)nc(Br)c1O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)c1cc(C(C)(C)C)nc(Br)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a solution of the above bromopyridine (2.74 g, 9.07 mmol) in acetonitrile/methanol (9:1, 33 mL) was added N,N-diisopropylethylamine (2.50 mL, 14.2 mmol) followed by (trimethylsilyl)diazomethane (2.0M in hexane, 7.0 mL, 14.2 mmol). The red solution was stirred 0.5 h at room temperature then concentrated in vacuo. The residue was dissolved in methylene chloride, washed with saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-bromo-6-tert-butyl-3-methoxy-isonicotinic acid ethyl ester (2.65 g, 93%) as a red oil which was utilized without further purification.
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].[Li][CH3:16].[BH4-].[Na+].Cl>CO.C1COCC1>[NH2:12][CH:11]([C:10]1[CH:9]=[CH:8][C:7]([C:3]2([C:1]#[N:2])[CH2:6][CH2:5][CH2:4]2)=[CH:14][CH:13]=1)[CH3:16]
Reactant: N#Cc1ccc(C2(C#N)CCC2)cc1
Reactant: [Li]C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)c1ccc(C2(C#N)CCC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
4-(Cyanocyclobutyl)benzonitrile (335 mg, 1.84 mmol) is mixed with THF (10.0 mL) and cooled to −78° C. under N2 gas. MeLi (1.15 mL, 1.84 mmol, 1.60M in Et2O) is added, and the mixture is stirred at −78° C. for 15 minutes. A mixture of NaBH4 (70.0 mg, 1.84 mmol) in MeOH (10.0 mL) is added, and the solution is warmed to 0° C. for 1 hour. 1N HCl (40.0 mL) is added, and the solution is concentrated to dryness on the rotovaporator. The product is purified by HPLC: Gilson prep pumps, flow rate: 30 ml/min, column: Synergi Gemini (5u) 21.2×50 mm (high pH), mobile phase: A=water (10 mM NH4CO3) B=MECN, (95.0 mg, 0.475 mmol, 26%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.23 (d, J=6.64 Hz, 3H) 1.90-2.06 (m, 1H) 2.16-2.35 (m, 1H) 2.52-2.64 (m, 2H) 2.64-2.78 (m, 2H) 4.00 (q, J=6.64 Hz, 1H) 7.36 (d, J=8.59 Hz, 2H) 7.42 (d, J=8.20 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[OH:1][CH2:2][CH2:3][S:4]([C:5]1[S:6][C:7]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:9]=1)=[O:34]
Reactant: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)CCO)sc2-c2ccc(OC)cc2)cc1

Procedure:
5.0 g of 2-(2-hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole are dissolved in 100 ml of methylene chloride and, while stirring, 2.56 g of m-chloroperbenzoic acid are added in portions. The mixture is then stirred for 15 minutes and subsequently extracted by shaking twice with dilute sodium carbonate solution. The aqueous phase is then washed with methylene chloride. The organic phases are combined, dried over magnesium sulphate and concentrated to dryness by evaporation. The crude product is dissolved in 10 ml of ethyl acetate, precipitated with 30 ml of diethyl ether, filtered with suction, washed with diethyl ether, dried under reduced pressure and, to purify further, made into a slurry with 50 ml of diethyl ether, filtered again and dried at 0.01 mbar and 100° to constant weight. 2-(2-hydroxyethanesulphinyl)-4,5-bis-(p-methoxyphenyl)-thiazole is obtained in the form of a pale yellow oil, Rf value 0.12 (silica gel thin layer/toluene:ethyl acetate 1:1); IR-spectrum: νSO =1060 cm-1 (3% in CH2Cl2).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C1COCC1.Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2>C(O)(=O)C>[C:1]1([CH2:7][CH2:8][O:9][C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[NH:19][CH:20]=[N:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccccc1
Reactant: Clc1ncnc2nc[nH]c12
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1ccc(CCOc2ncnc3nc[nH]c23)cc1
Temperature: 60 °C
Yield: 62 %

Procedure:
2-Phenylethanol (13 ml) was stirred under nitrogen and sodium (0.75 g, 32.36 mmol) was added. The reaction was heated to 60° C. When no sodium remained, anhydrous THF (18 ml) and 6-chloropurine (1.0 g, 6.47 mmol) were added. After refluxing under nitrogen for 5 h, the reaction mixture was allowed cool to room temperature and neutralised with glacial acetic acid. The THF was removed and the remaining alcohol was removed in vacuo. The product was recrystallised from ethanol and isolated as a white crystalline solid (962 mg, 62%), m.p. 209-210° C.; (Found: C, 64.57; H, 5.12; N, 23.54. Calc. for C13H12N4O: C, 64.99; H, 5.03; N, 23.34%); νmax (cm−1) 3135,3063, 3031, 2948, 2897, 2797, 2672, 2583 (NH, C—H); δH (200 MHz, d6-DMSO) 8.483 (1H, s, C(2)H or C(8)H), 8.365 (1H, s, C(2)H or C(8)H), 7.366-7.194 (5H, m, Ph), 4.741 (2H, t, J=7.0 Hz, OCH2), 3.134 (2H, t, J=7.0 Hz, CH2Ph); m/z 240 (M+, 11%), 149 ([M—Bn]+, 11%), 136 ([M—CH2CH2Ph]+, 87%), 119 ([M—OCH2CH2Ph]+, 40%), 104 ([CH2CH2Ph]+, 100%), 91 (BN+, 37%), 77 (Ph+, 55%), 69 (48), 65 (15), 51 (26).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][CH2:14][O:15][CH2:16][C:17]1[CH:18]=[C:19](/[CH:23]=[CH:24]/[CH2:25][CH2:26][C:27]#[N:28])[CH:20]=[CH:21][CH:22]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[CH3:12][O:13][CH2:14][O:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:23]2[O:9][CH:24]2[CH2:25][CH2:26][C:27]#[N:28])[CH:20]=[CH:21][CH:22]=1
Reactant: COCOCc1cccc(/C=C/CCC#N)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCOCc1cccc(C2OC2CCC#N)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
m-Chloroperbenzoic acid (3.77 g) was added to a solution of (E)-5-(3-((methoxymethoxy)methyl)phenyl)pent-4-enenitrile (2.08 g) in ethyl acetate (20 mL) at room temperature, and the mixture was stirred at 80° C. for 1 hr. Saturated aqueous sodium thiosulfate solution was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.07 g) as a colorless oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(C)([O-])C.[K+].F[C:19]1[CH:20]=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25].O>CN(C)C=O.Cl>[CH3:27][O:26][C:24]([C:23]1[CH:28]=[C:19]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:20]=[CH:21][C:22]=1[N+:29]([O-:31])=[O:30])=[O:25]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(C(=O)OC)c1
Temperature: 60 °C
Reaction time: 25 h

Procedure:
To a solution of diethyl malonate (8.04 ml, 52.9 mmol) in N,N-dimethylformamide (30.0 ml), potassium tert-butoxide (5.94 g, 52.9 mmol) was added, and, after complete dissolution, methyl 5-fluoro-2-nitrobenzoate (4.69 g, 26.5 mmol) obtained in Reference Example 107 was added. The reaction mixture was stirred at 60° C. for 25 hours and poured onto an iced water, made acidic with iN hydrochloric acid, and then extracted with ethyl acetate. After the extract was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure to give the title compound as an oil. This product was used in the next reaction without further purification.
Reaction SMILES: CN1CCOCC1.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:12]2[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 0 °C

Procedure:
N-methylmorpholine (60 g, 65 mL, 0.6 mol) is dissolved in DCM (100 mL), to which 1-methylpiperazine (30.5 g, 0.3 mol) is added. The reaction is cooled to 0° C., after which a solution of 4-bromo-benzenesulfonyl chloride (75.8 g, 0.296 mol) in DCM (100 mL) is added dropwise. The reaction is allowed to warm to RT overnight. The reaction mixture is then concentrated and water (1 L) is added. The solids that are formed are filtered and the filtrate is extracted with EtOAc (500 mL). The organic layer is washed with saturated brine, dried over MgSO4, filtered and concentrated to afford 1-(4-bromo-benzenesulfonyl)-4-methyl-piperazine as a pale yellow solid: LC/MS 321.0 (M+1); 1H NMR (400 MHz, CDCl3) δ 2.3 (s, 3 H) 2.5 (m, 4 H) 3.0 (m, 4 H) 7.6 (dt, J=8.8, 2.0 Hz, 2 H) 7.7 (dt, J=8.8, 2.1 Hz, 2 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:26]=[CH:25][C:11]([CH:12]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:29]=1[NH:36][C:37](=[O:40])[CH2:38]Cl.C(OCC)(=O)C>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]([N:19]2[CH2:20][CH2:21][N:22]([CH2:38][C:37](=[O:40])[NH:36][C:29]3[C:28]([CH3:27])=[CH:33][C:32]([CH3:34])=[CH:31][C:30]=3[CH3:35])[CH2:23][CH2:24]2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:25][CH:26]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cc1cc(C)c(NC(=O)CCl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(NC(=O)CN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)c(C)c1
Temperature: 80 °C
Reaction time: 7.5 h

Procedure:
2 g of anhydrous potassium carbonate were added to a mixture of 192.6 mg of 1-(4-chlorobenzhydryl)piperazine and 142.7 mg of N-(2,4,6-trimethylphenyl)chloroacetamide dissolved in 20 ml of N,N-dimethylformamide, and the reaction mixture was stirred at 80° C. for 7.5 hours. At the end of this time, ethyl acetate was added to the mixture, and the organic layer was separated. The organic layer was washed three times with water, and then the solvent was evaporated off under reduced pressure. The residue was subjected to silica gel thin layer chromatography using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the developing solvent, to afford a purified 1-(4-chlorobenzhydryl)-4-(2,4,6-trimethylphenylcarbamoylmethyl)piperazine.
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21](=O)[O:22]C4C=CC=CC=4)=[CH:14][CH:13]=3)[N:10]=[C:9]([C:30]([F:33])([F:32])[F:31])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[C:1]1([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:43][S:40]([C:37]4[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=4)(=[O:42])=[O:41])=[O:22])=[CH:16][CH:17]=3)[N:10]=[C:9]([C:30]([F:31])([F:32])[F:33])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1)Oc1ccccc1
Reactant: NS(=O)(=O)c1ccncc1
Product: O=C(NCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1)NS(=O)(=O)c1ccncc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 4 of Example 78) and pyridine-4-sulfonamide: 1H-NMR (CDCl3) δ 8.79-8.73 (2H, m), 7.64-7.62 (2H, m), 7.31-7.07 (9H, m), 6.76 (1H, s), 6.24 (1H, br.s), 3.46-3.37 (2H, m), 2.81-2.72 (2H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[N+:21]([C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:29]([C:27]2[S:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)=[O:30])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])s1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and 5-nitro-thiophene-2-carboxylic acid.