Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=3)=[O:29])=[C:14]([F:19])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.1 %

Procedure:
To a solution of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide (177 mg, 0.68 mmol) in toluene (3 mL) was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate (150 mg, 0.68 mmol). The mixture was stirred at rt for 72 h. The reaction was concentrated under reduced pressure and the residue was triturated with diethylether. The resulting solid was collected by filtration and dried in vacuo for 4 h to afford the title compound (155 mg, 0.32 mmol; 47% yield); 1H-NMR (DMSO-d6) 2.78 (d, J=4.9, 3H), 7.03-7.08 (m, 1H), 7.16 (dd, J=2.6, 5.6, 1H), 7.32 (dd, J=2.7, 11.6, 1H), 7.39 (d, J=2.5, 1H), 7.60 (s, 2H), 8.07-8.18 (m, 2H), 8.50 (d, J=5.7, 1H), 8.72 (s, 1H), 8.74-8.80 (m, 1H), 9.50 (s, 1H); MS (HPLC/ES) 483.06 m/z=(M+1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]([CH3:18])=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[Br:1][C:12]1[C:13]([O:16][CH3:17])=[N:14][CH:15]=[C:10]([Cl:9])[C:11]=1[CH3:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)c(Cl)cn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(Cl)c(C)c1Br
Temperature: 50 °C
Reaction time: 20 h
Yield: 97.4 %

Procedure:
20.2 g (114 mmol) of N-bromosuccinimide was charged to a N,N-dimethylformamide (DMF) 15 ml solution of 7.2 g (46 mmol) of 5-chloro-2-methoxy-4-methylpyridine, followed by stirring at 50° C. for 20 hours. A diluted sodium thiosulfate aqueous solution was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and subjected to filtration on the pad of a silica gel cake, and the solvent was distilled off under reduced pressure to obtain 10.6 g (yield: 97%) of 3-bromo-5-chloro-2-methoxy-4-methylpyridine (melting point: 44 to 45° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH:43]([OH:59])[CH2:44][N:45]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:52]([N:45]([CH2:44][CH:43]([OH:59])[CH2:42][NH:41][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: NCC(O)CN(Cc1ccccc1)c1ccccc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCC(O)CN(Cc1ccccc1)c1ccccc1

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (85 mg, 0.15 mmol) and 1-amino-3-(N-benzylanilino)-2-propanol (47 mg, 0.18 mmol) according to Method C with HPLC purification to the title compound (23 mg) as a diasteromeric mixture. IR (KBr) 3414, 1654 cm−1; HRMS m/z 768.3382 (calc. of monoisotopic mass for C42H48N4O10 gives 768.3370).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[CH3:25][S:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[C:27]([S:26][CH3:25])[CH:28]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: CSc1cccc(N)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(SC)c3)c2cc1OC
Yield: 38.2 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 167.1 mg (1.2 mmol) of 3-(methylthio)aniline to give 134.1 mg (38.2%) of the product as an off white solid, m.p.>250° C., mass (electrospray, m/e): M+H 351.9.
Reaction SMILES: [Li]CCCC.[Si]([CH:10]=[N+:11]=[N-:12])(C)(C)C.[O:13]=[C:14]1[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:16][CH2:15]1>C1COCC1>[C:22]([O:21][C:19]([NH:18][C@@H:17]([CH2:16][CH2:15][C:14](=[O:13])[CH:10]=[N+:11]=[N-:12])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:20])([CH3:23])([CH3:25])[CH3:24]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CCC(=O)C=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
n-BuLi was added dropwise to a solution of TMSCHN2 (690 mL, 1.38 mol) in dry THF (3 L) (600 mL, 1.5 mol) at −78° C., and the mixture was stirred at −78° C. for 30 min. The mixture was then transferred to a solution of (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (300 g, 1.17 mol) in dry THF (3 L) via cannula, and the mixture was stirred at −78° C. for 30 min. The reaction mixture was then quenched with sat. NH4Cl solution, and extracted with DCM three times. The combined organic layer was concentrated in vacuum and the crude product was purified by silica gel column chromatography (3:1 petroleum ether:EtOAc) to afford (S)-ethyl 2-((tert-butoxycarbonyl)amino)-6-diazo-5-oxohexanoate (262 g, 75%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].BrC[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([O:11][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH:8]=[C:7]([O:12][C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[CH:6]=1)[CH3:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(C#N)cc2)cc(Oc2ccc(C#N)cc2)c1
Temperature: 35 °C
Yield: 83 %

Procedure:
To a solution of 3,5-dihydroxy benzoic acid ethyl ester 1.2 g (6.58 mmol), dissolved in 10 ml DMF, was added K2CO3 3.63 g (26.32 mmol) followed by 4-bromomethyl-benzonitrile 5.16 g (26.32 mmol) in 5 ml of DMF at 20° C. The reaction mixture was allowed to attain RT and then heated to 35° C. for 8 h. The solvent was removed under reduced pressure and the residue was dissolved in 200 ml of ethyl acetate. The organic layer was washed with brine and water. Organic phase was dried over anhydrous sodium sulphate and solvent was removed under reduced pressure. The crude product was subjected to column chromatography and eluted using hexane:ethyl acetate (8:2) to afford 2.1 g of purified product. 1H NMR (DMSO-d6): 1.3 (3H, t), 4.3 (2H, q), 5.3 (4H, s), 7.0 (1H, s), 7.18 (2H, s), 7.64 (4H, d), 7.86 (4H, d).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24].S(Cl)(Cl)=O>>[C:1]([O:9][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][CH:23]([CH3:24])[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)CCCCCCCCCCCCCO
Solvent: O=S(Cl)Cl
Product: CC(C)CCCCCCCCCCCCCOC(=O)c1cccnc1
Temperature: 80 °C

Procedure:
Iso-hexadecyl nicotinate was prepared from nicotinic acid and a commercial material, iso-hexadecyl alcohol, obtained from Farbwerke Hoechst AG. The general method of Example 1 was used except that the temperature after thionyl chloride addition was maintained at 80° C. for 2 hours, and after the esterification reaction the solution was cooled and washed with 0.5M sodium hydroxide, 0.5M hydrochloric acid and water. The solution was treated with activated carbon (2.5% on the expected weight of product) at 50° C. for 1 hour, filtered and the solvent removed under reduced pressure. The light brown oil had an estimated purity of 93.4% and was distilled (boiling range 141°-146° C. at 0.03 mm mercury pressure) to provide a product of 99.8% estimated purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].[CH:12]1([CH2:15]Br)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:15][CH:12]2[CH2:14][CH2:13]2)[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: OCc1c(F)cc(O)cc1Cl
Reactant: BrCC1CC1
Product: OCc1c(F)cc(OCC2CC2)cc1Cl
Yield: 77 %

Procedure:
This compound was prepared from 3-Chloro-5-fluoro-4-hydroxymethyl-phenol and cyclopropylmethylbromide according to the procedure described in Example 179 to give the product as a yellowish oil (305 mg, 77%); MS (EI): 230.1 (M)+.
Reaction SMILES: [CH:1]([C:4]1[C:5]([S:14][C:15]#[N:16])=[CH:6][C:7]([N+:11]([O-])=O)=[C:8]([NH2:10])[CH:9]=1)([CH3:3])[CH3:2].[H][H]>[Ni].C1COCC1>[CH:1]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[CH:6][C:5]=1[S:14][C:15]#[N:16])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)c1cc(N)c([N+](=O)[O-])cc1SC#N
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)c1cc(N)c(N)cc1SC#N

Procedure:
5-Isopropyl-2-nitro-4-thiocyanato-phenylamine (prepared in Example QQ-1; 7.83 g, 33 mmol) was hydrogenated using Raney nickel (2 g) and THF (100 mL) in the presence of hydrogen (50 psi) as described in General Method 3. MS(APCI): 208(M+H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]([C:24]2[C:28]3[CH:29]=[N:30][CH:31]=[C:32]([F:33])[C:27]=3[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=2)=[O:23])[CH:19]=[N:20][CH:21]=1>>[F:33][C:32]1[C:27]2[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=[C:24]([C:22]([C:18]3[CH:17]=[C:16]([NH:15][C:10](=[O:12])[CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=4)[CH:21]=[N:20][CH:19]=3)=[O:23])[C:28]=2[CH:29]=[N:30][CH:31]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C(F)(F)F)cc3)c2)c2cncc(F)c21

Procedure:
Prepared according to Method M (Example 206) using 4-trifluoromethylphenylacetic acid and (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 1, Preparation 26).
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:40])([F:39])[C:5]1[CH:6]=[C:7]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:8][N:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:12]([C:20](=[O:31])[CH2:21][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[O:23])[N:11]=[N:10]1.O>C(Cl)Cl>[F:40][C:4]([F:3])([F:39])[C:5]1[CH:6]=[C:7]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:8][N:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:12]([C:20](=[O:31])[CH:21]([Br:1])[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[O:23])[N:11]=[N:10]1
Reactant: BrBr
Reactant: O=C(CC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1)c1ccccc1Cl
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1Cl)C(Br)C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
Add bromine (28 μL, 0.54 mmol) to a mixture of 1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propane-1,3-dione (256 mg, 0.463 mmol) in 1:1 CH2Cl2:H2O (4 mL). Stir mixture at RT for 30 min, then dilute with additional CH2Cl2 (20 mL) and wash with NaHCO3 (20 mL). Dry, filter, and concentrate the organic layer to give the title compound (287 mg, 98%). MS (IS) 553.2 (M+1), MS (ES−) 551.2 (M−1). 1HNMR (400 MHz, CDCl3): δ 7.80 (m, 1H), 8.53 (m, 1H), 7.85 (m, 2H), 7.63 (m, 1H), 7.46 (m, 7H), 7.04 (s, 1H), 5.60 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([Mg]Br)C.[Br:15][C:16]1[C:17]([N:19]([CH3:24])[C:20](=[O:23])[C:21]=1Br)=[O:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:15][C:16]1[C:17]([N:19]([CH3:24])[C:20](=[O:23])[C:21]=1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[NH:7][CH:6]=1)=[O:18]
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: CN1C(=O)C(Br)=C(Br)C1=O
Agent: CC[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: Cc1ccc2[nH]cc(C3=C(Br)C(=O)N(C)C3=O)c2c1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 86.8 %

Procedure:
To a solution of 5-methylindole (90 mg, 0.78 mmol) dissolved in THF (3 mL) was added 0.95M ethylmagnesium bromide (0.83 mL, 0.78 mmol) at 40° C., and the whole was stirred at 40° C. for 45 minutes. Successively, thereto was added a solution of 2,3-dibromo-N-methylmaleimide (100 mg, 0.39 mmol) dissolved in THF (5 mL), followed by stirring under heating and refluxing for 3 hours. After 20% aqueous citric acid solution (1 mL) was added thereto under ice cooling and the whole was stirred, THF was removed by concentration under reduced pressure and the resulting concentrate was extracted with ethyl acetate. The extract was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=1:1) to obtain 2-bromo-3-(5-methyl-1H-indol-3-yl)-N-methylmaleimide (108 mg, 86.3%) as red solids.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11](=O)(=[O:14])([OH:13])[OH:12].[CH2:16]=[O:17].[OH-].[Ca+2].[OH-]>O>[C:9]1([S:11]([OH:14])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:16]=[O:17]
Reactant: c1ccc2ccccc2c1
Reactant: O=S(=O)(O)O
Agent: C=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(O)c1cccc2ccccc12
Temperature: 25 °C

Procedure:
1 mol of naphthalene (128.2 g) was reacted with 1.28 mol of sulfuric acid (125.5 g) for 3 hours at 150° C. to 160° C. To the product (sulfonate) were added 44 g of water, and formalin (37% formaldehyde in water) in such amount as equal to 0.98 mol of formaldehyde dropwise over 3 hours at 90° C. The mixture was reacted for condensation for 10 hours at 100±2° C. The mixture was cooled to room temperature, neutralized to pH 5 with calcium hydroxide, and filtrated to remove generated precipitates (gypsum), resulting in an aqueous solution of a naphthalenesulfonic acid-formaldehyde condensate (B-1). The polymer was dried for 24 hours at 105° C. The aqueous solution was adjusted to an intended concentration to be used according to need.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[N:24][C:23]=2[CH:32]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[N:24][C:23]=3[CH:32]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: ClCc1ccc2oc(-c3cccs3)nc2c1
Reactant: Oc1cccc(CCCCn2ccnc2)c1
Product: c1cc(CCCCn2ccnc2)cc(OCc2ccc3oc(-c4cccs4)nc3c2)c1
Yield: 70 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(3-hydroxyphenyl)butyl]imidazole was allowed to react with 5-chloromethyl-2-(2-thienyl)benzoxazole to give 5-[3-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)benzoxazole. The yield was 70%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 97-98° C.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](Cl)(=[O:13])[CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:3]1([CH2:2][CH2:1][NH:9][C:10](=[O:13])[CH2:11][CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCCc1ccccc1

Procedure:
The title compound was prepared in a reaction between phenethylamine (12.1 g, 100 mmol), propionyl chloride (9.25 g, 100 mmol) and triethylamine (20 ml) in methylene chloride (200 ml). The product (10.1 g) was used without purification; MS [M+H]+ 178.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][Cl:21])[CH:16]=[C:11]2[CH:10]=[C:9]1[C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:21][CH2:20][CH2:19][CH2:18][O:17][C:15]1[CH:16]=[C:11]2[CH:10]=[C:9]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:31])([F:30])[CH2:28][CH2:29]3)=[O:23])[NH:8][C:12]2=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(OCCCCl)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc2cc(OCCCCl)cnc2[nH]1)N1CCC(F)(F)CC1
Temperature: 0 °C

Procedure:
The solution of 1.3 g (2.8 mmol) 5-(3-chloro-propoxy)-2-(4,4-difluoro-piperidine-1-carbonyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester in 15 ml dichloromethane was cooled down to 0° C., then 4.2 ml (6.3 g, 55.5 mmol) trifluoroacetic acid was added and the cooling bath was removed. After 1.5 hours the solution was cooled again down to 0° C. and 60 ml of an aqueous 1M sodium hydroxide solution was added slowly. The solution was extracted three times with dichloromethane, the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and 50 ml n-heptane) was added. The dichloromethane was evaporated at a rotary evaporator and the resulting suspension was filtered and washed with n-heptane and the colorless solid (0.92 g, 93%) was dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7](Cl)(=[O:9])=[O:8].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH3:22])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][N:21]([CH3:22])[S:7]([C:6]2[CH:5]=[C:4]([Cl:11])[S:3][C:2]=2[Cl:1])(=[O:9])=[O:8])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: CNCCc1ccc(F)cc1
Product: CN(CCc1ccc(F)cc1)S(=O)(=O)c1cc(Cl)sc1Cl

Procedure:
From 2,5-dichlorothiophene-3-sulfonyl chloride (755 mg) and [2-(4-fluorophenyl)ethyl]methylamine (the compound of Preparation Example 14) (510 mg), the title compound (1.14 g) was obtained as a colorless oily matter, in the same way as Preparation Example 41.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Sc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: Clc1ccc(Sc2ccnc(Cl)c2)cc1
Yield: 84.8 %

Procedure:
Using the method of Example 3, Step A, 4-chlorobenzenethiol (912 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to afford 2-chloro-4-(4-chlorophenylthio)pyridine (1.37 g, 85% yield) as an oil. 1H NMR (CDCl3) δ 8.14 (d, 1H), 7.48 (d, 2H), 7.46 (d, 2H), 6.90 (s, 1H), 6.85 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25]>O1CCCC1>[CH2:17]([N:14]1[CH2:13][CH2:12][CH:11]([N:10]2[CH2:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:24]2=[O:25])[CH2:16][CH2:15]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1ccccc1CCNC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2CCN1C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
A stirred solution of [2-(2-amino-phenyl)-ethyl]-(1-benzyl-piperidin-4-yl)-amine (0.44 g, 1.42 mmol) in tetrahydrofuran (5 mL) at 0° C. was treated with carbonyl diimidazole (0.23 g, 1.42 mmol). The reaction was stirred for 30 min at 0° C. and at reflux for 1 h. After cooling to room temperature, the solvent was evaporated and the residue purified by column to afford 100 mg (21%) of the desired product. LC/MS: tR=1.29 min, 336.34 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][N:14]3[N:18]=[C:17]([NH2:19])[CH:16]=[N:15]3)[CH:8]=2)[O:6]CCO1.[C:20]1([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][N:14]2[N:18]=[C:17]([NH:19][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:32])[CH:16]=[N:15]2)[CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccnc(Cn3ncc(N)n3)c2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1ccnc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)c1

Procedure:
Following general procedure A followed by N, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30][NH:2][CH2:3][C:4]3[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=3)=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(C(=O)OC)cc3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure A using methyl 4-(aminomethyl)benzoate hydrochloride and 4-[(4-butylphenyl)ethynyl]benzaldehyde as a white solid (54%). 1H NMR (CDCl3, 300 MHz) δ 8.02 (d, J=8.3 Hz, 2H), 7.51 (d, J=7.9 Hz, 2H), 7.44 (m, 4H), 7.33 (d, J=7.9 Hz, 2H), 7.17 (d, J=7.9 Hz, 2H), 3.92 (s, 3H), 3.87 (s, 2H), 3.82 (s, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.3 Hz, 3H). M+ (ESI): 412.4. HPLC, Rt: 4.28 min (Purity: 99.4%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1)([O-:20])=[O:19].C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:28]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=2)=[S:29])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(NC(=S)Nc2ncccc2OCc2c(F)cccc2Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (7.01g, 0.028 mol), 4nitrophenyl isothiocyanate (5.31g, 0.03 mol) and toluene (50 ml) was heated under reflux for 2 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 11.07 g (86%), m.p. 214° 215 ° C.