Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29].[N:40]1([CH2:46][C:47]2[CH:48]=[C:49]([CH:55]=[CH:56][CH:57]=2)[O:50][CH2:51][CH2:52][CH2:53][NH2:54])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:28]([NH:54][CH2:53][CH2:52][CH2:51][O:50][C:49]2[CH:55]=[CH:56][CH:57]=[C:47]([CH2:46][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:48]=2)=[O:29])[CH3:25])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCCCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCCCCCCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.59 g (1.6 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,7-heptanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propylamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=647 ([M+H]+, 7), 229 (100); IR (KBr): 1634 cm-1 (C=O). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanol/ether; m.p.: 112° C. (isopropanol/ether).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])#N>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([CH3:23])[CH:26]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: CN1CCCC1=O
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was taken 100 mg of 3-(3-chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one (0.31 mmol, 1.00 eq), 61 mg of 3-cyanobenzoyl chloride (0.37 mmol, 1.20 eq), and 500 uL NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield N-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-3-methyl-N-(2-methoxy-ethyl)-benzamide. MS (ES) M+H expected=444.0, found=444.2.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[C:7]([CH2:16][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)=[O:5].[C:36](=O)([O-])[O-].[Na+].[Na+].C=O>C(Cl)(Cl)Cl.O>[CH:16]([C:7]1[N:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:6]=1[C:4]([O:3][CH3:2])=[O:5])=[CH2:36]
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Br-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=Cc1nc(C(F)(F)F)ccc1C(=O)OC
Reaction time: 1.5 h

Procedure:
5.7 g (10 mmol) of (3-methoxycarbonyl-6-trifluoromethylpyridine-2-ylmethyl)triphenyl-phosphonium bromide are dissolved at room temperature in a 2-phase system of 25 ml of chloroform and 2.1 g (20 mmol) of sodium carbonate and reacted, in 10 ml of water, with a 35% aqueous solution of 1.7 g (20 mmol) of formaldehyde. After 1.5 hours, the organic phase is separated off and filtered through silica gel. Methyl 2-vinyl-6-trifluoromethylnicotinate is obtained as an oil, 1H-NMR (CDCl3): 8.31, d, CH, 7.10, dd, CH, 7.09, d, CH, 6.68, dd, CH, 5.68, dd, CH, 3.97 ppm, s, OCH3.
Reaction SMILES: [Br:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(OC(C)C)(C)C>>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[C:12]([O:4][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[CH2:2][Br:1])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: OC(CBr)c1cccc(Cl)c1
Solvent: CC(C)OC(C)C
Product: CC(=O)O[C@H](CBr)c1cccc(Cl)c1
Product: O[C@@H](CBr)c1cccc(Cl)c1

Procedure:
To 100 mg (0.4 mmol) of 2-bromo-1-(3-chlorophenyl)ethanol were added 30 mg of Lipase QL (available from Meito Sangyo Co., Ltd.) and 40 mg (0.4 mmol) of acetic anhydride. Diisopropyl ether was added to the mixture to make the total volume to 1 ml. The reaction mixture was then allowed to undergo reaction at a temperature of 35° C. for 72 hours. After the termination of the reaction, the enzyme was removed by filtration. The resulting filtrate was then concentrated under reduced pressure. The concentrated solution was analyzed by 1H-NMR. As a result, it was found that (R)-2-bromo-1-(3-chlorophenyl) ethanol and (S)-2-bromo-1-(3-chlorophenyl)ethyl acetate had been produced in a proportion of 2:3. The concentrated solution was then separated by a thin layer silica gel chromatography. As a result, (R)-2-bromo-1-(3-chlorophenyl)ethanol ([α]D20 =-25.6°, C=1.05) and (S)-2-bromo-1-(3-chlorophenyl)ethyl acetate ([α]D20 =+40.4°, C=0.60) were obtained. The optical purity of (R)-2-bromo-1-(3-chlorophenyl)ethanol thus obtained was analyzed by Chiral HPLC. The results were 100% ee.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[CH:11]=[C:10]([C:12]2[N:16]3[N:17]=[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)[CH:9]=[N:8]1>C(O)(C(F)(F)F)=O.O>[NH:8]1[CH:9]=[C:10]([C:12]2[N:16]3[N:17]=[C:18]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)[CH:11]=[N:7]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cnc3ccc(N4CCOCC4)nn23)cn1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1n[nH]cc1-c1cnc2ccc(N3CCOCC3)nn12
Yield: 32.8 %

Procedure:
The product from step C (284 mg, 0.71 mmol) was heated to 60° C. in a mixture of TFA (5 mL) and water (1 mL) for 1 h. Upon cooling the reaction mixture was concentrated and partitioned between ethyl acetate and saturated sodium carbonate solution. The solid that formed at the solvent interface was removed by filtration and dried under vacuum to provide the pure title compound (63 mg, 33%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.89 (d, J=9.9 Hz, 1H), 7.84 (s, 1H), 7.15 (d, J=9.9 Hz, 1H), 3.79 (t, J=3.9 Hz, 4H), 3.52 (t, J=4.3 Hz, 4H); 13C NMR (125 MHz, DMSO-d6) δ 155.2, 136.1, 135.8, 128.4, 125.8, 125.1, 121.8, 109.2, 108.6, 65.6, 46.0; HPLC tR=13.6 min (Luna), >99%; ES-MS: (M+H)=271 m/z.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@:5]([CH3:10])([C:7]([O-:9])=[O:8])[CH2:4][O:3]1.[Li+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1([CH3:11])[O:6][C@:5]([CH3:10])([C:7]([O:9][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:8])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@](C)(C(=O)[O-])O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@](C)(C(=O)OCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the compound prepared in Example 180 (5.9 g) in N,N-dimethylformamide (hereinafter abbreviated to DMF) (120 mL) were added benzyl bromide (4.3 mL) and potassium carbonate (9.9 g) and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered through Celite (trade name) and concentrated in vacuum condition to remove DMF. To the obtained residue was added water and the organic layer was extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate and concentrated in vacuum condition. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=6:1→4:1) to give the title compound (6.1 g) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1O.CC1CCCC(C)C1=O.[NH3:19]>[Pt]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH2:19]
Reactant: Cc1cccc(C)c1O
Reactant: N
Agent: [Pt]
Agent: CC1CCCC(C)C1=O
Product: Cc1cccc(C)c1N
Temperature: 300 °C
Reaction time: 4 h

Procedure:
In a pressure reaction vessel place one mole part of 2,6-dimethylphenol, 0.1 mole part of 2,6-dimethyl cyclohexanone, 0.007 mole part of platinum (0.1 weight per cent on silica-alumina support) and 3 mole parts of ammonia (as 29 per cent aqueous ammonium hydroxide). Seal the vessel and heat to 300°C and stir at this temperature for 4 hours. Cool and filter off the catalyst for recycle. Distill the filtrate to obtain the product 2,6-dimethyl aniline in good yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH2:26][CH2:27][F:28])[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH2:26][CH2:27][F:28])[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OCCF)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(OCCF)ccc2C(=O)O)CC1
Yield: 39.3 %

Procedure:
Using a procedure similar to that of Example 6-E, methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2-fluoroethoxy)benzoate (7.28 g) is hydrolyzed using LiOH.H2O (1.78 g, 2.2 equivalents), water (20 mL) and THF (60 mL) at 60-65° C. to afford the acid (2.76 g, 40%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[C:18]([CH3:24])[N:17]=3)=[CH:13][C:12]=2[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.C(O)(=O)C.[Na]>CO.Cl.CCOCC>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[N:17]=[C:18]([CH3:24])[C:19]([CH2:20][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)=[CH:22][CH:23]=3)=[CH:13][C:12]=2[CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CNC1
Reactant: Cc1nc(-c2cc3cc(Cc4ccccc4)ccc3o2)ccc1C=O
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc(-c2cc3cc(Cc4ccccc4)ccc3o2)ccc1CN1CC(C(=O)O)C1
Temperature: 24 °C
Reaction time: 1 h

Procedure:
A suspension of 6-(5-benzylbenzofuran-2-yl)-2-methylnicotinaldehyde (160 mg, 489 μmol) and 3-azetidinecarboxylic acid (49.4 mg, 489 μmol) in MeOH (8 mL) and glacial acetic acid (44.0 mg, 733 μmol) was stirred at 24° C. for 1 h, treated with sodium borocyanohydride (15.4 mg, 244 μmol), and stirred for 2 h. The mixture was diluted with 30 mL of 1M HCl in Et2O and evaporated. Purification of the residue by RP-HPLC to give title compound as an off-white solid [hS1P1 EC50=420 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (s, 2H), 7.55-7.53 (m, 2H), 7.43 (s, 1H), 7.28-7.18 (m, 6H), 4.04 (s, 2H), 3.59 (s, 2H), 3.45-3.23 (m, 8H). MS (ESI) m/z: Calculated: 412.5; Observed: 413.3 (M++1).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]([OH:14])=O)[N:4]=1.[CH3:15][CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C=O)C>[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]([N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:24][CH:16]2[CH3:15])=[O:14])[N:4]=1
Reactant: CC1Cc2ccccc2N1
Reactant: COc1cc(Cl)nc(CC(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc(Cl)nc(CC(=O)N2c3ccccc3CC2C)n1
Temperature: 20 °C

Procedure:
In a three-necked flask, under argon, 4 g of the sodium salt of (4-chloro-6-methoxypyrimidin-2-yl)acetic acid (example 8b, step 3b) and 2.6 g of 2-methylindoline (6872-06-6, Aldrich) are placed in 3 ml of pyridine and 60 ml of DMF. The heterogeneous solution obtained is stirred at ambient temperature (20° C.), then N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride is added and stirring is maintained for 20 hours. The reaction mixture is concentrated in a rotary evaporator under vacuum, 100 ml of water are added, extraction is carried out with 3 times approximately 50 ml of dichloromethane, washing is carried out with 50 ml of saturated NaCl solution, drying is carried out over MgSO4 and filtration is carried out through a VF filter. The compound obtained is chromatographed on silica gel (40-63 μm), elution being carried out with dichloromethane. The fractions containing the expected compound are combined and evaporated. The compound obtained is triturated from diisopropyl ether, filtration is carried out, and drying is carried out at 20° C. 2-(4-Chloro-6-methoxypyrimidin-2-yl)-1-(2-methyl-2,3-dihydroindol-1-yl)ethanone is isolated (2.6 g) in the form of a solid (yield 46%) which is used as it is in the next step.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]=[CH:10][C:11](=[CH2:13])[CH3:12].O>CCCCCC>[CH3:12][C:11]1[CH2:13][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH2:9][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: C=CC(=C)C
Solvent: O
Solvent: CCCCCC
Product: CC1=CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
Bis-trifluoromethanesulphonimide (70, 5 mg, 0.25 mmol) was stirred in hexane (4 ml) at room temperature. Benzaldehyde (510 μl, 5.0 mmol) and isoprene (750 μl, 7.5 mmol) were added and the mixture stirred at room temperature overnight. Water (5 ml) was added and the aqueous layer was extracted with hexane (3×3 ml). The combined organic layers were filtered through celite and analysed by glc. A yield of 42% of 4-methyl-6-phenyl-5,6-dihydropyran was observed.
Reaction SMILES: [Na][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[I-].[Na+].Cl[CH2:14][C:15](=[O:17])[CH3:16]>CC(C)=O>[C:5]([CH:4]([CH2:14][C:15](=[O:17])[CH3:16])[C:3](=[O:10])[CH3:2])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C[Na]
Reactant: CC(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC(C)=O)C(C)=O

Procedure:
To a stirred and refluxing solution of ethyl sodioacetoacetate (0.5 mole, 78g.) and sodium iodide (1g.) in dry acetone (250 ml.) was added chloroactone (0.54 mol. 50g.) over a period of ten minutes. After one hour the acetone was distilled from the reaction mixture and the residue was diluted with 400 ml. water. The preciptated oil was extracted with ether and the ether removed to yield the intermediate 3-carbethoxy-2,5-hexanedione (75g.). The intermediate (26.4g.) was cyclized by heating under reflux over 5 g. anhydrous oxalic acid for 11/4 hours. The crude ester was saponified by heating under reflux for 45 minutes with potassium hydroxide (26g.) in methanol (200 ml.). The methanol was removed, the residue dissolved in water and the solution acidified to yield 2,5-dimethyl-3-furoic acid (18g.), m.p. 130°-133°.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[NH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1.[CH3:16]O>>[ClH:4].[NH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH2:8]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CO
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Product: COC(=O)[C@H]1CC[C@@H](N)CC1
Product: Cl
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
5 cm3 of sulfonyl chloride are added dropwise to 50 cm3 of methanol cooled to −10° C. After stirring for 10 minutes at 20° C., 5.0 g of cis-4-aminocyclohexane-1-carboxylic acid are slowly added in fractions. After stirring for 2 hours at ,20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 20° C., to give 7.5 g of methyl cis-4-aminocyclohexane-1-carboxylate hydrochloride, in the form of a white powder.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.CN1CCOCC1.Cl>[Cu].C(OCC)(=O)C.CN(C)C=O>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[CH:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1I
Reactant: Nc1ccc(Cl)cc1
Agent: [Cu]
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1Nc1ccc(Cl)cc1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 20 %

Procedure:
To N,N-dimethylformamide 0.9 mL solution of 2-iodo-4-phenoxybenzoic acid 45 mg were added 4-chloroaniline 27 mg, copper powder 5 mg and N-methylmorpholine 0.036 mL, and it was stirred under application of pressure at 180° C. for 15 minutes. After the reaction mixture was cooled to room temperature, 1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 65-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-chloroanilino)-4-phenoxybenzoic acid 9 mg of white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:13]1[C:14](=[O:28])[CH2:15][C:16]([CH3:27])([CH3:26])[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]=1[OH:19])(=O)[CH2:9][CH2:10][CH3:11].Cl.[CH2:30]([O:33][NH2:34])[CH:31]=[CH2:32]>C(O)C>[CH2:30]([O:33][N:34]=[C:8]([C:13]1[C:14](=[O:28])[CH2:15][C:16]([CH3:27])([CH3:26])[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]=1[OH:19])[CH2:9][CH2:10][CH3:11])[CH:31]=[CH2:32]
Reactant: C=CCON
Reactant: CCCC(=O)C1=C(O)C(c2ccccc2)C(C)(C)CC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=CCON=C(CCC)C1=C(O)C(c2ccccc2)C(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Triethylamine (1.2 g) was added to a solution of 2-butyryl-5,5-dimethyl -3-hydroxy-4-phenyl cyclohex-2-ene-1-one (2.8 g) and O-allylhydroxylamine hydrochloride (1.2 g) in ethanol (50 ml). After stirring at ambient temperature overnight, the ethanol was evaporated in vacuo, water was added to the residue and the aqueous solution extracted with methylene chloride. After drying the organic extracts over anhydrous magnesium sulphate, the methylene chloride was evaporated in vacuo. The residue was chromatographed on a silica gel column using 5% (v/v) diethyl ether-methylene chloride as eluant to give the title compound (2.1 g) as a viscous, colourless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[F:23][C:24]1[CH:25]=[CH:26][C:27]2[N:33]3[CH:34]=[N:35][C:36]([C:37](=[N:39]O)[NH2:38])=[C:32]3[C@@H:31]3[CH2:41][CH2:42][N:30]3[C:29](=[O:43])[C:28]=2[CH:44]=1>CN(C)C=O>[F:23][C:24]1[CH:25]=[CH:26][C:27]2[N:33]3[CH:34]=[N:35][C:36]([C:37]4[N:39]=[C:4]([CH2:3][N:2]([CH3:7])[CH3:1])[O:5][N:38]=4)=[C:32]3[C@@H:31]3[CH2:41][CH2:42][N:30]3[C:29](=[O:43])[C:28]=2[CH:44]=1
Reactant: CN(C)CC(=O)O
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN(C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1
Temperature: 90 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
1.75 g (17 mmol) of N,N-dimethylglycine were dissolved in 20 ml of N,N-dimethylformamide and treated portionwise with 3.08 g (15 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 evolution the solution was stirred at 70° for 30'. Then, 4.02 g (15 mmol) of (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at 90° C. overnight. By evaporation of the solution, chromatography of the residue on 240 g of silica gel while eluting with methylene chloride/methanol 19/1 and crystallization from ethyl acetate there were obtained 1.35 g (24%) of (S)-7-fluoro-12,12a-dihydro-1-[5-(dimethylaminomethyl)-1,2,4-oxadiazol-3-yl]-9H,11H-azeto-[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 187°-190°, which was converted into the hydrochloride of m.p. 150°-155°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[CH3:8][C:9]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:15]#[N:16])([CH3:11])[CH3:10].C(N(C)C(C)C)(C)C>C(Cl)Cl>[CH3:24][C:21]([C:18]1[CH:17]=[C:14]([CH:13]=[C:12]([C:9]([CH3:11])([CH3:10])[CH3:8])[C:19]=1[O:20][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:15]#[N:16])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(C#N)cc(C(C)(C)C)c1O
Reactant: COCCOCCl
Agent: CC(C)N(C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1c(C(C)(C)C)cc(C#N)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Methoxyethoxymethyl chloride (4.1 g, 0.032 mole) is added dropwise to a 0° C. mixture of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzonitrile (Louis A. Cohen, Journal of Organic Chemistry 22, 1333, 1957) (5.0 g, 0.022 mole) and diisopropylaminomethane (4.2 g, 0.032 mole) in methylene chloride (50 ml). The mixture is allowed to warm to room temperature and stir 18 hours. The solution is diluted with methylene chloride (25 ml) and washed with water (25 ml), cold 2M HCl (20 ml), saturated aqueous NaCl, and dried over MgSO4. Filtered and concentrated in vacuo to obtain 6.7 g (6.9 g theor., 97%) of 3,5-bis(1,1-dimethylethyl)-4-(2-methoxyethoxy)methoxy]benzonitrile as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=O)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.[NH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=[N:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: NN1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccc(C=NN5CCCC5)cc34)cc2Cl)c1
Yield: 81.4 %

Procedure:
In a mixture of 1 mL of tetrahydrofuran and 0.1 mL of water were dissolved 40 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-formylquinazoline (IV-1) and 13 mg of 1-amino-pyrrolidine hydrochloride, followed by a reaction at room temperature overnight. After the reaction, aqueous saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was dehydrated by passing through Presep (registered trademark), and the filtrate was concentrated. The concentrated residue was purified by chromatography (eluting with hexane:ethyl acetate=2:1→1:1) using an amino column to obtain 38 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(pyrrolidin-1-yliminomethyl)quinazoline (IX-1) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([S:7][CH3:8])[CH2:5][NH:4][CH2:3]1.[CH:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11]>CO>[CH3:9][C:10]([CH3:13])([CH3:12])[CH:11]=[N:1][C@H:2]1[C@H:6]([S:7][CH3:8])[CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)C=O
Reactant: CS[C@@H]1CNC[C@H]1N
Solvent: CO
Product: CS[C@@H]1CNC[C@H]1N=CC(C)(C)C
Reaction time: 0.5 h

Procedure:
1.32 g (10 mmol) of trans-3-amino-4-methylthiopyrrolidine are initially introduced into 5 ml of methanol, and 1.23 ml (11 mmol) of 97% strength pivalaldehyde are added dropwise, after which the temperature rises from 25° to 36° C. The mixture is subsequently stirred for a further 30 minutes, without cooling, the batch is then concentrated and the residue is distilled. Yield: 1.50 g (75% of theory), boiling point: 63° C./0.07 mbar.