Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.CN1[CH2:9][CH2:8][N:7]([C:10](=[O:34])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[C:22]([NH:27][C:28]4[S:29][CH:30]=[C:31]([CH3:33])[N:32]=4)=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:14]=2)CC1.C(N(CC)CC)C.[NH:42]1[C:46](CCN)=[CH:45][N:44]=[CH:43]1.Cl>>[ClH:1].[ClH:1].[NH:42]1[C:46]([CH2:9][CH2:8][NH:7][C:10](=[O:34])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[C:22]([NH:27][C:28]4[S:29][CH:30]=[C:31]([CH3:33])[N:32]=4)=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:14]=2)=[CH:45][N:44]=[CH:43]1
Reactant: NCCc1cnc[nH]1
Reactant: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)N3CCN(C)CC3)c2)n1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)NCCc3cnc[nH]3)c2)n1
Yield: 86.9 %

Procedure:
2-(3-((2-(4-Methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetic acid trifluoroacetate (prepared according to Example 27; 70 mg, 0.14 mmol), triethylamine (0.10 mL, 0.72 mmol) ethyl chloroformate (0.035 mL, 0.36 mmol) and 2-(1H-imidazol-5-yl)ethanamine (80 mg, 0.72 mmol) were reacted according to the method of Example 29 to provide N-(2-(1H-imidazol-5-yl)ethyl)-2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetamide dihydrochloride (32.7 mg, 40.0% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 9.02 (d, 1H), 8.39 (t, 1H), 8.00 (dd, 1H), 7.66 (d, 1H), 7.40 (s, 1H), 7.30 (m, 2H), 7.19 (d, 1H), 7.16 (dd, 1H), 6.93 (s, 1H), 6.88 (dd, 1H), 5.33 (s, 2H), 4.52 (s, 2H), 3.45 (q, 2H), 2.86 (t, 2H), 2.35 (s, 3H). Mass spectrum (apci) m/z=465.2 (M+H-2HCl).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][NH:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([OH:11])=[O:10].[CH3:18]O>>[CH3:18][O:10][C:9](=[O:11])[CH2:8][CH:7]([NH:6][CH3:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNC(CC(=O)O)c1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CNC(CC(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Thionyl chloride (30 ml) was added at 0°-5° C. to a stirred solution of 3-methylamino-3-phenylpropionic acid (39 g) in anhydrous methanol and the mixture stirred at ambient temperature for 5 hours. The solution was evaporated under reduced pressure and the residue treated with 2N sodium carbonate (350 ml). The solution was extracted with dichloromethane (2×100 ml). The combined extracts were washed with water (250 ml) dried over magnesium sulphate and evaporated under reduced pressure to give methyl-3-methylamino-3-phenylpropionate (36.9 g) as a clear orange oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH2:7]([NH:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)[CH3:8].C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[CH3:6][O:5][C:3](=[O:4])[CH2:2][N:9]([CH2:7][CH3:8])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1
Reactant: COC(=O)CBr
Reactant: CCNc1cccc(O)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC(=O)OC)c1cccc(O)c1
Temperature: 100 °C

Procedure:
Methyl bromoacetate (10.7 g, 70 mmole), 3-(ethylamino) phenol from above (4.8 g, 35 mmole), and ethyl diisopropyl amine (4.45 g, 35 mmole) were combined in 25 ml of toluene. The mixture was heated at 100° C. for 30 min. and then evaporated under vacuum and chromatographed on a silica gel column using 5% (v/v) methanol/methylene chloride. The combined fractions were washed with saturated sodium bicarbonate and neutralized with 0.1N HCL. The combined fractions were dried over Na2SO4 and evaporated to give 7.24 g of N-ethyl-N-3-hydroxyphenyl glycine methyl ester.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:8]=[C:9]([CH:34]=[CH:35][C:36]=1[N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[CH2:10][NH:11][C:12](=[O:33])/[C:13](=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]2)=[C:21]([O:31][CH3:32])[CH:20]=1)/[CH2:14][CH2:15][CH2:16]Cl.[H-].[Na+].O>C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[C:9]([CH:34]=[CH:35][C:36]=1[N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14]/[C:13](=[CH:18]\[C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)/[C:12]1=[O:33]
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NCc2ccc(N3CCOCC3)c(F)c2)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C2\CCCN(Cc3ccc(N4CCOCC4)c(F)c3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.9 %

Procedure:
To a DMF (4 mL) solution of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl]benzylidene)valeric acid [3-fluoro-4-(morpholin-4-yl)benzyl]amide (135 mg), sodium hydride was added at 0° C. (40% mineral oil content, 35.6 mg) was added, and the reaction solution was allowed to be warmed to room temperature and agitated for 45 minutes. The reaction solution was cooled to 0° C. after confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After washed with a saturated saline solution the organic layer, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 113 mg of the title compound was obtained by purifying the obtained residue by silica gel chromatography (elution solvent; ethyl acetate→ethyl acetate:ethanol 90:10). The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH3:15])[CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br-].[C:18]([CH2:21][CH2:22][CH2:23][CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:20])=[O:19].[H-].[Na+].CC(O)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:7]([CH3:15])[CH:8]1[CH2:13][CH2:12][C:11](=[CH:24][CH2:23][CH2:22][CH2:21][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(=O)CC1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(=CCCCC(=O)O)CC1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
5 g (21.99 mmol) Methyl-(4-oxo-cyclohexyl)-carbamic acid tert-butyl ester and 12.68 g (28.59 mmol) (4-Carboxy-butyl)-triphenyl-phosphonium bromide were dispended in 50 ml DMF. In small portions 2.49 g (57.2 mmol, 55%) NaH were added and the slurry was diluted by adding 50 ml DMF. The mixture was stirred at RT over night, 10 ml AcOH were added and the solvent was evaporated under reduced pressure. The residue was dissolved in ether and water, and the inorganic layer was extracted with ether. The combined organic phases were dried over and the crude materil was purified by column chromatography with ETOAc/hexane to give 5.86 g (83%)5-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexylidene]-pentanoic acid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].OO.O.O.O.O.O.S([O-])([O-])(=[O:33])=S.[Na+].[Na+].O>C(O)(=O)C>[CH2:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)=[O:33])=[CH:18][CH:17]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O=S([O-])([O-])=S
Reactant: CCCCOc1ccc(Sc2ccc(OCCCC)cc2)cc1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1ccc(S(=O)c2ccc(OCCCC)cc2)cc1
Reaction time: 12 h
Yield: 90 %

Procedure:
In 200 g of acetic acid was dissolved 30 g of bis(4-butoxyphenyl) sulfide obtained in Synthesis Example 1-17. While the solution was maintained at an internal temperature of 30° C., 8.8 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 12 hours, after which under ice cooling, a mixture of 0.9 g sodium thiosulfate pentahydrate and 30 g water was added dropwise to quench the reaction. The solution was combined with 200 g of methylene chloride and 50 g of water for extraction. The organic layer was separated, washed with water, and concentrated in vacuum. On subsequent purification by silica gel chromatography, 28 g of the target compound, bis(4-butoxyphenyl) sulfoxide was obtained as amorphous solid. Yield 90%.
Reaction SMILES: CCN(CC)CC.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(OC([N:26]1[CH2:29][CH2:28][C@H:27]1[CH2:30][O:31][C:32]1[CH:33]=[C:34]([C@H:38]2[CH2:40][C@@H:39]2[CH2:41][CH2:42][OH:43])[CH:35]=[N:36][CH:37]=1)=O)(C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:43][CH2:42][CH2:41][C@H:39]2[CH2:40][C@@H:38]2[C:34]2[CH:35]=[N:36][CH:37]=[C:32]([O:31][CH2:30][C@@H:27]3[CH2:28][CH2:29][NH:26]3)[CH:33]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CCO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@H]2C[C@@H]2c2cncc(OC[C@@H]3CCN3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
4-(Dimethylamino)pyridine (DMAP; 14 mg, 0.11 mmol, 0.02 equiv.), Et3N (0.24 mL, 1.7 mmol, 3.0 equiv.), and p-toluenesulfonyl chloride (164 mg, 0.86 mmol, 1.5 equiv.) were added to a stirred solution of 2-[(1R,2S)-2-[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]ethanol (200 mg, 574 μmol) in dry CH2Cl2 (5 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, then diluted with CH2Cl2 (50 mL). The organic phase was washed with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. 2-[(1R,2S)-2-[5-[(2(S)-Azetidinyl)methoxy]-3-pyridyl]cyclopropyl]ethyl p-toluenesulfonate (Rf=0.4, 50% EtOAc in petroleum ether) was obtained by CC (237 mg, 82%) and was directly used for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[NH:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[O:16].NCCC(O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:20]2[NH:14][C:15](=[O:16])[NH:17][C:18]2=[O:19])[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11]
Reactant: O=C1CNC(=O)N1
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: NCCC(=O)O
Product: COc1cc(C=C2NC(=O)NC2=O)cc(OC)c1O
Yield: 75.7 %

Procedure:
Prepared according to the procedure described in Example 90 using 3,5-dimethoxy-4-hydroxybenzaldehyde (5.6 g, 30 mmoles), hydantoin (3.0 g, 30 mmoles), and β-alanine (1.4 g, 16 mmoles), to afford the pure product (6.0 g), mp 296°-297° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:18])[C:5]([C:15]([OH:17])=O)=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CC(N(C)C)=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:23][O:22][N:21]([CH3:20])[C:15]([C:5]1[C:4](=[O:18])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:6]=1)=[O:17]
Reactant: CNOC
Reactant: COc1cn(-c2ccccc2)nc(C(=O)O)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1cn(-c2ccccc2)nc(C(=O)N(C)OC)c1=O
Temperature: 50 °C
Yield: 83.4 %

Procedure:
Under an argon atmosphere, 5-methoxy-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxylic acid (40 g) was dissolved in dimethylacetamide (600 mL) by heating to 50° C., and ice-cooled. With stirring, N,O-dimethylhydroxylamine hydrochloride (23.7 g), 1-hydroxybenzotriazole (21.9 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.6 g) were added, and triethylamine (81.4 mL) was added, and the mixture was allowed to warm to room temperature and stirred for 96 hr. To the reaction mixture was added ethyl acetate, and an insoluble material was filtered off. The filtrate was concentrated under reduced pressure to dryness, and the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol) to give the title compound (39.2 g) as white crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[OH-].[Na+].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>C(OCC)C>[CH2:10]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H](CO)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)[C@H](CO)NCc1ccccc1
Temperature: 5 °C
Yield: 39.3 %

Procedure:
A 5 L 3-neck round bottom flask was charged with L-serine (313 g, 3.0 mol) and 2N sodium hydroxide solution (1.5 L). Stirring was begun and benzaldehyde (322.4 g, 3.0 mol) added. After 15 minutes at room temperature the solution was cooled to 5° C. and sodium borohydride (35.0 g, 0.93 mol) was added in small portions so as to maintain the temperature below 10° C. Once the addition was complete the solution was allowed to warm to room temperature and stir for 2 h. At this point, a second portion of benzaldehyde (322.4 g, 3.0 mol) was added and the solution stirred for 15 minutes. The solution was cooled to 5° C. and sodium borohydride (35.0 g, 0.93 mol) added, again maintaining the temperature below 10° C. The reaction mixture was then warmed to room temperature and stirred for 2 h. Diethyl ether (1 L) was added, the solution stirred 5-10 minutes and the ether layer separated. The pH of the aqueous layer was then adjusted to 6 with 37% hydrochloric acid. Filtration of the resulting solids and recrystallization of the wet cake from water afforded 230 g (40%) of (S)-(+)-N-benzylserine after drying at 45° C. overnight.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:15][S-:16].[Na+].CCOC(C)=O.Cl>C1COCC1>[CH3:15][S:16][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: C[S-]
Reactant: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1cc(C(=O)O)cc(C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a suspension of 2-chloro-6-(trifluoromethyl)isonicotinic acid (0.1 g, 443 μmol, prepared according to F. Cottet, M. Schlosser, Eur. J. Org. Chem. 2004, 18, 3793-3798) in THF (5 mL) was added sodium thiomethoxide (155 mg, 2.22 mmol, CAS RN 50615-16-2) and the reaction mixture was heated to 70° C. (oil bath temperature) for 15 hours. After cooling down to room temperature, EtOAc (5 mL) and 1M aqueous HCl (2 mL) were added and the reaction mixture was stirred at room temperature for 30 min. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give the desired compound as an off-white solid (0.105 g; 99%) which was used in the next step without further purification. MS (ESI): m/z=236.01 [M−H]−.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].[C:18]1([CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH:31]=[CH:32][CH:33]=[O:34])[CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C1CCCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:33]([OH:34])[CH:32]=[CH:31][CH:28]1[CH2:27][CH2:26][N:25]([CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:30][CH2:29]1
Reactant: O=CC=CC1CCN(Cc2ccccc2)CC1
Reactant: c1ccc2scnc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: OC(C=CC1CCN(Cc2ccccc2)CC1)c1nc2ccccc2s1
Reaction time: 0.25 h

Procedure:
A solution of benzothiazole (0.243 g, 1.8 mmol) in 5 ml of dry THF was treated with 1.5 M lithium diisopropylamide in cyclohexane (1.45 ml) at -78° C. and stirred at that temperature for 15 minutes. A solution of 3-[1-(phenyl-methyl)-4-piperidinyl]propenal (452 mg, 1.97 mmol) in 3 ml of dry THF was added at -78° C. and stirred at that temperature for 30 minutes. The mixture was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give a thick yellow oil in a quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][NH:10][C:9]2=[O:19])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Cl)[CH3:21]>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]1=[O:19])[CH3:21]
Reactant: O=c1[nH]cc(-c2ccccc2)n1-c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCCCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O

Procedure:
The product is obtained as described in example 1 from 1.35 g NaJ (80% suspension in mineral oil), 12.2 g of 1-(4-chlorophenyl)-5-phenyl-4-imidazolin-2-one, 100 cc. of DMF, 8.7 g of 7-chloroenanthic acid ethyl ester and 1.35 g of NaJ. Eluant in chromatographic purification: hexane/ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1S(O)(=O)=O.[OH-:13].[K+]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:13]
Reactant: [OH-]
Reactant: Cc1ccc(N)c(S(=O)(=O)O)c1
Agent: [K+]
Product: Cc1ccc(N)c(O)c1

Procedure:
The Na salt of 2-amino-5-methyl-benzenesulphonic acid is reacted with 80% by weight of KOH to give the K salt of 2-amino-5-methyl-phenol (300° C.; 15 to 20 bar; 3h), the molar ratio of KOH to 2-amino-5-methyl-benzenesulphonic acid preferably being from 10:1 to 15:1. The reaction mixture is diluted to a content of approximately 5% by weight of 2-amino-5-methyl-phenol by direct expansion at 300° C. into water, or by pumping water into the autoclave after prior cooling to approximately 200° C. The resulting alkaline suspension of the K salt of 2-amino-5-methyl-phenol is metered into water at the same time as 36% by weight aqueous HCl at 90° C. at a pH of from 0.5 to 1.0. All the SO2 is expelled from the resulting, aqueous, approximately 4% by weight 2-amino-5-methyl-phenol hydrochloride solution using nitrogen or by applying a vacuum, the solution is if necessary clarified using activated carbon to remove tarry constituents, and the 2-amino-5-methyl-phenol is precipitated out by neutralization of the hydrochloric acid solution, for example using aqueous sodium hydroxide at a pH of from 4.5 to 6.0, and isolated in the usual manner, for example by filtration and washing with water.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][OH:24].CCOC(/N=N/C(OCC)=O)=O.[C:38]([O:42][N:43]=[C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[C:51](O)[CH:52]=2)[O:47][C:46]([C:55]2[N:56]=[CH:57][C:58]3[C:63]([CH:64]=2)=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:45]1)([CH3:41])([CH3:40])[CH3:39].[Na]>O1CCCC1>[C:38]([O:42][N:43]=[C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([CH2:20][N:21]3[CH2:25][CH2:1][O:24][CH2:23][CH2:22]3)[CH:52]=2)[O:47][C:46]([C:55]2[N:56]=[CH:57][C:58]3[C:63]([CH:64]=2)=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:45]1)([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(O)cc12
Reactant: CN(C)CCO
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(CN3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.1 %

Procedure:
To a cold solution of triphenylphosphine (110 mg, 0.41 mmol) in tetrahydrofuran (3 ml) under argon were successively added 2-dimethylamino-ethanol (30 μl, 0.27 mmol), a solution of diethylazodicarboxylate (40% in toluene, 190 μl, 0.41 mmol) and 6-hydroxy-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (100 mg, 0.27 mmol). The solution was stirred at room temperature for 18 hours. The mixture was poured onto a saturated solution of sodium hydrogenocarbonate and extracted three times with dichloromethane. The organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness to yield 2-isoquinolin-3-yl-6-(morpholin-4-yl-methyl)-chromen-4-one O-tert-butyl oxime (30 mg, 22%) as a yellow solid after purification by flash chromatography over silica gel (dichloromethane/methanol: 0-20%)
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:23][CH3:24])=[O:5])C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:4](=[O:5])[C:6]3[CH:7]=[N:8][C:9]4[C:10]([O:23][CH3:24])=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[N:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:33]2=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCCCC3)c12
Yield: 68.8 %

Procedure:
3-(3-Chloro-phenyl)-1-cyclohexyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (30 mg) was prepared from 4-cyclohexylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-chloro-3-isocyanato-benzene (0.15 mmol) following general procedure C. LCMS: m/z 436 [M+1]+.
Reaction SMILES: N[C:2]1[C:10](C(F)(F)F)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].COC(=O)C1C=CC=CC=1I>CO.O>[C:4]([OH:6])(=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Agent: COC(=O)c1ccccc1I
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1
Yield: 51 %

Procedure:
Similar reaction of 2-amino-3-trifluoromethylbenzoic acid and methyl-2-iodobenzoate by the reported method [Rewcastle and Denny, Synth. Comm, 1987, 17, 309] gave 3-trifluoromethyl-2-[(2-methoxycarbonyl)phenyl)amino]benzoic acid (51%), mp (MeOH/H2O) 113-115° C. 1H NMR [(CD3)2SO] δ 3.89 (s, 3 H, CO2CH3), 6.35 (d, J=8.5 Hz, 1 H, ArH), 6.78 (t, J=7.5 Hz, 1 H, ArH), 7.30 (ddd, J=7.8, 7.8, 1.6 Hz, 1 H, ArH), 7.59 (t, J=7.8 Hz, 1 H, ArH), 7.88 (dd, J=8.0, 1.5 Hz, 1 H, ArH), 8.03 (d, J=7.4 Hz, 1 H, ArH), 8.07 (d, J=8.07 Hz, 1 H, ArH), 9.49 (s, 1 H, NH), 13.15 (br s, 1 H, COOH). Anal. (C16H12F3NO2) C, H, N, F.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[C:23]([C:25]#[N:26])[C:22]4[N:27]=[CH:28][NH:29][C:21]=4[CH:20]=3)=[CH:15][C:14]=2[C:30]([F:33])([F:32])[F:31])[CH2:7][CH2:6]1.[CH:34](N(C(C)C)CC)(C)C>C1COCC1>[C:1]([N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]#[N:26])[C:22]3[N:27]=[CH:28][N:29]([CH3:34])[C:21]=3[CH:20]=2)=[CH:15][C:14]=1[C:30]([F:32])([F:31])[F:33])[CH:5]1[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1nc(-c2ccc(OCCCNC3CC3)c(C(F)(F)F)c2)cc2[nH]cnc12
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)N(CCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (0.010 ml) was added dropwise to a solution of 6-(4-(3-(cyclopropylamino)propoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg) and diisopropylethylamine (0.042 ml) in THF (2 ml). The reaction mixture was stirred at room temperature for 1 hour. The product was then purified by acidic prep HPLC to give 6-{4-[3-(N-acetyl-N-cyclopropylamino)propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile.