Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][NH2:36])[N:30]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:22])[F:20])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[N:35]([C:31]2[N:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[N:36]=[C:25]([CH3:26])[CH:24]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Reactant: NNc1cccnn1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cccnn1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with pyridazin-3-yl-hydrazine (CAS Reg. No. 40972-16-5) to give the title compound as colorless oil. MS (ESI): m/z=496.3 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:19][NH2:20].O>CCO>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[C:9]3[S:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:16])[NH:19][N:20]=2)=[CH:3][CH:4]=1
Reactant: NN
Reactant: CCOC(=O)c1ccsc1C(=O)c1ccncc1
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccncc2)c2sccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
The mixture of ethyl 2-isonicotinoylthiophene-3-carboxylate (200 mg, 0.77 mmol) from example 2.2 in NH2NH2.H2O (2 mL) and EtOH (10 mL) was stirred at room temperature for 30 min. The mixture was filtered and the solid dried to obtain the title compound (150 mg, 85.1% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59])=[O:6]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)cc2F)c(O)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.5 %

Procedure:
The 2-fluoro-4-(1-phenoxyethyl)benzoic acid (150 mg, 0.514 mmol), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (353 mg, 0.84 mmol) was dissolved in 20 mL dichloromethane, and then added triethylamine (2 mL). After the mixture was stirred at room temperature for 10 minute, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.514 mmol, 96 mg) was added. The mixture was stirred at room temperature for 12 hours then washed with water (10 mL), extracted with dichloromethane (20 mL). The organic layer were concentrated and s purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 2-fluoro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide (70 mg, 47%). LCMS (M+H+) m/z: calcd 394.17. found 394. 1H NMR (300 MHz, CD3OD) δ 7.69 (t, J=6.1 Hz, 1H), 7.28-7.13 (m, 4H), 6.86-6.81 (m, 3H), 6.06 (s, 1H), 5.43-5.41 (m, 1H), 4.47 (s, 2H), 2.34 (s, 3H), 2.22 (s, 3H). 1.57 (d, J=6.6 Hz, 3H).
Reaction SMILES: CCO.[N+:4]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:16]([OH:18])=[O:17])([O-])=O>[Pd].CC(O)=O>[NH2:4][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)O)cc1C(=O)O
Reaction time: 16 h
Yield: 75.1 %

Procedure:
Into 20 mL EtOH and 20 mL HOAc was dissolved 2 g (9.48 mmol) 4-nitroisophthalic acid, and the solution was subjected to hydrogenation at atmospheric conditions over 1 g of 5% Pd on carbon. After 16 h, mixture was filtered, and filtrate was evaporated. The residue crystallized from methylene chloride-hexane, giving 1.29 g (75%) crystalline desired intermediate.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1.N1C=CN=C1.[C:28]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C.C(OCC)C>[Si:32]([O:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@H:4]1[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2cscn2)[C@@H](CO)OC1(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2cscn2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Reaction time: 2 h

Procedure:
(4S,5S)-Tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (0.096 g, 0.29 mmol) was dissolved in DMF (1 mL) with 1H-imidazole (0.026 g, 0.38 mmol) and tert-butylchlorodimethylsilane (0.053 g, 0.35 mmol). The reaction was stirred 2 hrs, diluted with diethyl ether and washed twice with water and once with brine. The organic layer was dried over magnesium sulfate and concentrated to furnish the title compound, which was used for the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)=[N:8][C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6]2.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([C:14]([F:17])([F:16])[F:15])[N:8]=1
Reactant: COc1ccc2c(O)nc(C(F)(F)F)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(C(F)(F)F)cc2c1
Temperature: 0 °C
Yield: 86 %

Procedure:
A solution of 6-methoxy-3-(trifluoromethyl)isoquinolin-1-ol (271 mg, 1.114 mmol) in POCl3 (3 mL) was refluxed for 4 h. After concentration, the residue was taken into a mixture of 100 mL of DCM and 50 mL of water, cooled to 0° C., neutralized with 3 N NaOH, dried over MgSO4, concentrated and purified via silica gel chromatography (5-20% EtOAc:Hex) to give the pure product 1-chloro-6-methoxy-3-(trifluoromethyl)isoquinoline (250 mg, 0.956 mmol, 86% yield) as an orange solid. MS: MS m/z 262.1(M++1).
Reaction SMILES: [C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[CH:20]=[O:21])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)([OH:24])N.P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+]>O1CCOCC1.O>[C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[C:20]([OH:24])=[O:21])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Reactant: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a suspension of 2-phenyl-1H-pyrrolo[2,3-f]isoquinoline-3-carbaldehyde G1 (0.55 mmol) in dioxane (6.8 mL) and water (2.4 mL), sulfamic acid (0.9 mmol) and sodium dihydrogen phosphate (2.33 mmol) were added. The mixture was cooled to 0° C. and sodium chlorite (0.95 mmol, dissolved in the minimum amount of water) was added. Other two additions of an equal amount of oxidant were made during 24 h of stirring, then the reaction was filtered and the solid product was washed with water and dried, resulting in 94% yield of the title compound. ESI (+) MS: m/z 289 (MH+); MS (ES−) 287. 1H NMR: 7.35-7.41 (m, 1H), 7.45-7.56 (m, 4H), 7.96 (d, J=9.00, 1H), 8.58 (d, J=9.00, 1H), 8.68 (d, J=5.17, 1H), 8.78 (d, J=5.17, 1H), 9.57 (s, 1H), 11.47 (bs, 1H), 13.54 (bs, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:21]([CH:22]=O)=[CH:20][C:11]3[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][O:14][C:10]=3[C:9]=2[F:24])[CH2:5][C@H:4]([CH3:25])[O:3]1.[NH:26]1[C:33](=[O:34])[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28]>C(O)C>[F:24][C:9]1[C:10]2[O:14][N:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]=2[CH:20]=[C:21]2[C:8]=1[N:6]1[CH2:5][C@@H:4]([CH3:25])[O:3][C@@H:2]([CH3:1])[C@@H:7]1[C:32]1([C:30](=[O:31])[NH:29][C:27](=[O:28])[NH:26][C:33]1=[O:34])[CH2:22]2
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Solvent: CCO
Product: CCOC(=O)c1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Yield: 89.5 %

Procedure:
Ethyl 6-((2R,6S)-2,6-dimethylmorpholino)-7-fluoro-5-formylbenzo[d]isoxazole-3-carboxylate (Intermediate 439, 350 mg, 1.00 mmol) and barbituric acid (141 mg, 1.10 mmol) were heated to refux in ethanol (45 ml) for 64 hours. The reaction was concentrated. The residue was dissolved in DCM, absorbed onto silica and purified by silica gel column chromatography using a gradient of DCM to ethyl acetate, to give the title compound (412 mg, 76%) as a racemic mixture.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br)([O-:19])=[O:18]>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-acetylpiperazine (5.0 g; 39.0 mmol) in THF (50 ml) was added triethylamine (5.6 ml; 39.0 mmol) and 3-nitrobenzylbromide (8.4 g; 39.0 mmol). The mixture was stirred at ambient temperature for 1 hour and the solvent was removed by evaporation. The residue was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulphate and evaporated under reduced pressure to leave 6m2, quantitatively.
Reaction SMILES: [O:1]1[C:13]2[C:4](=[CH:5][C:6]3[NH:10][C:9]([SH:11])=[N:8][C:7]=3[CH:12]=2)[O:3][CH2:2]1.Cl.Cl[CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH2:25][CH3:26])[C:20]([CH3:27])=[CH:19][N:18]=1.[OH-].[Na+]>C(O)C.O>[CH2:25]([O:24][C:21]1[C:20]([CH3:27])=[CH:19][N:18]=[C:17]([CH2:16][S:11][C:9]2[NH:10][C:6]3[CH:5]=[C:4]4[O:3][CH2:2][O:1][C:13]4=[CH:12][C:7]=3[N:8]=2)[C:22]=1[CH3:23])[CH3:26]
Reactant: CCOc1c(C)cnc(CCl)c1C
Reactant: Sc1nc2cc3c(cc2[nH]1)OCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)OCO4)c1C

Procedure:
5.82 g of 5H-1,3-dioxolo[4,5-f]benzimidazole-6-thiol were suspended in 200 ml of ethanol and the suspension was treated with 7.1 g 2-chloromethyl-4-ethoxy-3,5-dimethylpyridine hydrochloride while cooling with ice. Thereafter, a solution of 2.4 g of sodium hydroxide in 100 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 500 ml of methylene chloride. The solution was washed firstly with 250 ml of 1.5N sodium hydroxide solution and then with 3×300 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 150 g of silica gel using ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from acetonitrile gave 6-[[(4-ethoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5H-1,3-dioxolo[4,5-f]benzimidazole of melting point 184°-185°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][O:14][C:15](=[O:22])[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.Cl>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:18]2[CH2:19][CH2:20][CH2:21][CH:17]2[CH2:16][C:15]([O:14][CH3:13])=[O:22])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CC1CCCN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1CCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1.5 h

Procedure:
A solution of 3,4-dichlorobenzenesulfonyl chloride (1.88 g, 7.65 mmol) in DCM (15 ml) was added dropwise at 0° C. to a solution, cooled to 0° C., of pyrrolidin-2-ylacetic acid methyl ester (1.5 g, 8.4 mmol) in DCM (33 ml) and triethylamine was (2.66 ml, 21 mmol), and stirring was then carried out for 90 minutes at room temperature. 0.5 M HCl (20 ml) was then added, and stirring was carried out for a further 15 minutes. The organic phase was separated, washed with water and dried over sodium sulfate. The solvent was removed using a rotary evaporator and the product was used in the next stage without being purified further. Yield: 2.1 g (77%)
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)=[O:13]>[OH-].[Na+]>[F:1][C:2]1[C:3]([CH3:10])=[C:4](/[CH:5]=[CH:11]/[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C(C)=O)c1
Reactant: Cc1c(F)cccc1C=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(C(=O)/C=C/c2cccc(F)c2C)c1
Temperature: 21.5 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
To a stirred solution of 3-fluoro-2-methylbenzaldehyde (150 g, 1.2 mol) in IMS (600 mL) was added 3-methoxyacetophenone (163 g, 1.2 mol). NaOH (10% aq, 750 mL) was added over 40 min using a water bath to maintain a temperature between 18-25° C. The mixture was stirred vigorously at room temperature for 15 h and a thick precipitate was formed. The solid was isolated by filtration, broken up with a mortar and pestle, and washed IMS and water. After drying at 45° C. for 48 h, 273 g (84% yield), the desired product (E)-3-(3-fluoro-2-methylphenyl)-1-(3-methoxyphenyl)prop-2-en-1-one was obtained (characterized by LCMS and 1H NMR, LRMS (M+H+) m/z=271.1.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:11])[CH:17]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CN
Reactant: Clc1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-chloro-2-(pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. MS (ESI) 457 (M+H).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2([C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH2:11][O:10]2)=[CH:3][CH:2]=1.[Na].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>C(O)CC>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([OH:10])([CH2:11][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[C:12]([CH3:15])([CH3:16])[CH:13]=[CH2:14])=[CH:3][CH:2]=1
Reactant: c1c[nH]cn1
Reactant: C=CC(C)(C)C1(COc2ccc(-c3ccccc3)cc2)CO1
Agent: [Na]
Solvent: CCCO
Product: C=CC(C)(C)C(O)(COc1ccc(-c2ccccc2)cc1)Cn1ccnc1
Yield: 62.5 %

Procedure:
35.3 g (0.120 mol) of 2-(biphenyl-4-yloxymethyl)-2-(3,3-dimethylprop-1-en-3-yl)-oxirane, dissolved in 80 ml of n-propanol, were added to a boiling solution of 1 g (0.012 mol) of sodium propylate and 9 g (0.132 mol) of imidazole in 50 ml of n-propanol, in the course of 5 minutes. After the solution had been boiled under reflux for two days, the solvent was distilled off under reduced pressure, the residue was taken up in a mixture of 150 ml of ethyl acetate and 100 ml of dichloromethane, and the solution was washed with three times 50 ml of water. After the organic phase had been dried over anhydrous sodium sulphate, the solution was concentrated to dryness under reduced pressure. 10 ml of ethyl acetate were added to the solid residue, and the product was filtered off. 27.2 g (62.5% of theory) of 4-(biphenyl-4-yloxy-methyl)-3,3-dimethyl-4-hydroxy-5-(imidazol-1-yl)pent-1-ene were obtained in the form of colorless crystals of melting point 151° to 153° C. in this manner.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13](Cl)(Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:13](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)=[O:7]
Reactant: ClC(Cl)(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(N=C(Nc2ccc(C(=O)OC)cc2)c2ccccc2)cc1

Procedure:
N,N'-Bis(4-methoxycarbonylphenyl)benzamidine (1) was prepared from methyl 4-aminobenzoate and α,α,α-trichlorotoluene; pale-yellow crystals: mp 180°-182° C. 1H-NMR (CDCl3) 8.0-7.0 (m, 14H), 3.8 (s, 6H); IR (CDCl3) 3330, 1705, 1585; MS (m/e) 388 (M+), 238 (base).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10].BrBr.C(N(CC)CC)C.[NH2:27][C:28]([NH2:30])=[S:29].C(=O)([O-])O.[Na+]>C(O)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:8]1[S:29][C:28]([NH2:30])=[N:27][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:10]
Reactant: O=C(CC(=O)c1ccccn1)c1ccccn1
Reactant: NC(N)=S
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Nc1nc(-c2ccccn2)c(C(=O)c2ccccn2)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
1,3-Di(2-pyridyl)propane-1,3-dione (1.17 g, 5.15 mmol) was dissolved in acetic acid (20 mL), and bromine (856 mg, 5.35 mmol) was added thereto, followed by stirring at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was suspended in ethanol (30 mL), and triethylamine (0.750 mL, 5.38 mmol) and thiourea (416 mg, 5.47 mmol) were added thereto, followed by stirring under heating and reflux for 30 minutes. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with chloroform. The solvent was distilled away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=9:1) to afford the entitled Compound 630 (739 mg, 51%).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([C:34]1[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=1)(=[O:40])=[O:39]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccnc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. pyridin-3-sulfonyl chloride (12 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-]>CC(=O)CC>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:10]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[N:9]1
Reactant: c1ccc(-c2nn[nH]c2-c2ccccc2)cc1
Reactant: BrCCCCCCCCBr
Agent: O=C([O-])[O-]
Solvent: CCC(C)=O
Product: BrCCCCCCCCn1nnc(-c2ccccc2)c1-c1ccccc1

Procedure:
4,5-Diphenyl-1,2,3-triazole was treated with 1,8-dibromooctane and potassinm carbonate in butanone to give after chromatographic work up the title compound, m.p. 90°-91° C, Found: C, 64.0; H, 6.5; N, 10.1; Br, 19.8%; C22H26BrN3 requires: C, 64.1; H, 6.4; N, 10.2; Br, 19.4%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(Cl)[Cl:16]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([Cl:16])=[O:14]
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: ClC(Cl)Cl
Product: O=C(Cl)Cc1ccc2ccccc2c1

Procedure:
2-Naphthylacetyl chloride is prepared according to the method described in Example 8 using 2-naphthylacetic acid (2.47 g, 13.3 mmol) to give a yellow solid which is dissolved in chloroform (15 mL). This solution is added to a solution of (±)-trans-[2-(4-methyl-1-piperazinyl)]cyclohexanol (2.5 g, 12.6 mmol) in chloroform (10 mL), and the mixture is refluxed for 11 hours under nitrogen. The solvent is removed in vacuo, and the residue is partitioned between 1M hydrochloric acid (100 mL) and ether (60 mL). The ether layer is separated and the aqueous is washed with more ether (2×30 mL), and then basified by the addition of 50% sodium hydroxide solution. This is then extracted with ether (4×30 mL), and the combined ether extracts are washed repeatedly with water to remove any unreacted aminoalcohol. The ether containing the product is then dried over sodium sulfate, and the solvent is removed to leave the crude free ester. The free ester is dissolved in ether/dichloromethane (35 mL, 4:3) and converted to the dihydrochloride salt by treatment with an excess of HCl in the same solvent. The resulting solid is washed with ether and recrystallised from hot methanol to yield the title compound.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][CH:31]([CH2:35][CH3:36])[C:32](O)=[O:33]>>[CH3:30][CH:31]([CH2:35][CH3:36])[C:32]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:33]
Reactant: CCC(C)C(=O)O
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CCC(C)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 2-methylbutyric acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(2-methylbutyroyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 450 (M+H)+.