Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:24][OH:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[CH3:26][S:27]([O:25][CH2:24][C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCNC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)COS(C)(=O)=O
Reaction time: 3 h

Procedure:
A solution of Nα-Boc-Nδ-Cbz-ornithinol (363 mg) in dichloromethane (10 ml) at 0° C., under nitrogen atmosphere, was treated sequentially with methanesulfonyl chloride (110 μl, 1.4 eq) and triethylamine (200 μl, 1.4 eq). After 3 hrs, the solution was poured into dichloromethane and worked up as usual. The crude product, which is very pure (400 mg), is a white solid: 1H NMR (400 MHz, CDCl3) δ1.45 (s, 9H), 1.63 (m, 4H), 3.02 (s, 3H), 3.24 (m, 2H), 3.84 (m, 1H), 4.19 (dd, J=9.5; 3.7 Hz, 1H), 4.23 (d, J=9.5 Hz, 1H), 5.14 (s, 2H), and 7.39 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH3:14][CH:15]1[O:20][CH:19]([CH3:21])[CH2:18][NH:17][CH2:16]1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:17]2[CH2:16][CH:15]([CH3:14])[O:20][CH:19]([CH3:21])[CH2:18]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: CC1CNCC(C)O1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CC1CN(c2ccc([N+](=O)[O-])c(C(=O)O)c2)CC(C)O1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
The mixture of 5 g 2-nitro-5-chlorobenzoic acid and 15 ml 2,6-dimethylmorpholine is stirred at 120° C. for 6 hours. To the reaction mixture 150 ml of ethyl acetate is added. The precipitated yellow crystalline material is filtered off, dissolved in 15 ml water. The pH of the mixture is set to 6 with acetic acid. The precipitated material is filtered off, washed with water and dried, to obtain 4.2 g of the title compound (MH+:281).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.Cl>ClCCl.C(Cl)(Cl)Cl>[C:1]([NH:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1cnc2ccccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.5 %

Procedure:
Acetyl chloride (410 mg, 5.2 mmol) and triethylamine (620 mg, 6.2 mmol) were added to a solution of 3-aminoquinoline (710 mg, 4.9 mmol) in dichloromethane (50 ml) and the mixture was stirred at room temperature for 18 h. Chloroform (100 ml) was added, the mixture acidified with 1N hydrochloric acid (50 ml) and the phases separated. The aqueous phase was basified with 1N sodium hydroxide solution and extracted with chloroform/IPA (85:15, 175 ml). The organic extract was washed with water, brine, dried and reduced to afford 3-acetamidoquinoline (780 mg, 84%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH2:20][CH2:19]1)=[O:17].[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[C:35]([CH3:40])[CH:34]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([F:32])=[CH:34][C:35]=3[CH3:40])=[C:3]([C:16]([N:18]3[CH2:19][CH2:20][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24]4)[CH2:22][CH2:23]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Reactant: Cc1cc(F)ccc1N
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Yield: 86.8 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.07 g, 0.16 mmol) obtained in Example 108, step 2 and 4-fluoro-2-methylaniline (0.03 g, 0.24 mmol), the title compound (0.073 g, 88%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.[C:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:13].[PH5]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:14][C:12]#[N:13])[C:6]=2[CH:11]=1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1COc2ccc(Br)cc21
Agent: [PH5]
Solvent: Cc1ccccc1C
Product: N#CCc1coc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A suspension of 5-bromo-3-(2H)-benzofuranone (4.26 g) and cyanomethylene triphenylphosphorane (9.06 g) in dry xylene (100 ml) was heated at reflux for 24 h . A further quantity of the phosphorane (450 mg) was added and heating continued for a further period of 12 h. On cooling to ambient temperature the brown coloured suspension was evaporated to dryness in vacuo. Chromatography of the residue using dichloromethane:hexane (1:3) as eluant afforded a cream coloured product. Recrystallization (from ethanol) of the chromatographed material afforded the title compound as cream flakes, m.p. 120°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][CH3:18])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:17]([C:11]1([C:14]([OH:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:18]
Reactant: CCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1(C(=O)O)CCNCC1
Yield: 112.9 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)-4-ethylpiperidine-4-carboxylic acid (above step 1, 4.5 g, 12.96 mmol) in DCM (50 ml) was cooled to 0° C. After ten minutes, trifluoro acetic acid (6.0 g) was added and stirred the reaction at room temperature for about 6 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (2.3 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.48-1.58 (m, 2H); 2.14-2.18 (m, 2H); 2.64-2.73 (m, 2H); 2.86 (s, 2H); 3.01-3.07 (m, 4H); ES Mass: 158 (100%), [M+1].
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([CH2:7]Cl)=[CH2:6].[OH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CC(O)=O>CN(C)C=O.C1COCC1>[CH2:6]=[C:5]1[CH2:7][O:9][CH2:10][CH2:11][N:12]([C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[CH2:4]1
Reactant: C=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=C1COCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
60% Sodium hydride in oil (26 g, 0.65 mol, 2.17 eq) was added in one portion in a stream of argon at 5° C. to a solution of 3-chloro-2-(chloromethyl)prop-1-ene (35 mL, 0.3 mol, 1 eq) in dimethylformamide (500 mL). Then a solution of tert-butyl (2-hydroxyethyl)carbamate (48.3 g, 0.3 mol, 1 eq) in THF (500 mL) was added, and the reaction mixture was heated to 25° C. and stirred at this temperature for 2 h. The reaction mixture was then neutralized with glacial AcOH (4.5 mL) and evaporated in a water aspirator in vacuo at 45-55° C. using a 15-cm reflux condenser. The residue was poured with water (300 mL) and extracted with a mixture of ethylacetate (200 mL), hexane (100 mL) and chloroform (50 mL). The organic layer was separated and washed with water (2×100 mL) and brine. The combined aqueous layer was extracted with a mixture of ethylacetate (150 mL) and hexane (50 mL). The organic layer was separated and washed with water (2×100 mL) and brine. The extracts were filtered sequentially through silica gel (25 g) and sodium sulphate (50 mL), eluting with chloroform (100 mL). The filtrate was evaporated, and the residue was distilled in vacuo to give title compound as a colorless oil (bp 76-79° C. at 0.7 mm Hg) (35.8 g, 0.168 mol, 53%).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[CH2:5]([SH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:13]([CH3:16])([O-:15])=[O:14].N1CCCCC1>C1C=CC=CC=1.O>[CH2:5]([S:12][C:2]([CH3:4])([CH3:1])[CH2:16][N+:13]([O-:15])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)=O
Reactant: C[N+](=O)[O-]
Reactant: SCc1ccccc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: CC(C)(C[N+](=O)[O-])SCc1ccccc1
Reaction time: 48 h

Procedure:
Acetone (25 g), benzyl mercaptan (53 g), nitromethane (26.2 g), and piperidine (8 cm3) were dissolved in benzene (150 cm3) and the mixture heated under reflux with azeotropic removal of water. After 48 h the reaction mixture was allowed to cool and washed first with dilute hydrochloric acid, then with water. The remaining solution was dried (MgSO4) and the solvent then removed under reduced pressure to give the nitro system (76.5 g, 85%). This material was sufficiently pure to be used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](B(O)O)[CH:6]=[CH:5]2.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][N:17]=1>O1CCOCC1.O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:16]1[N:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][N:17]=1)[CH:6]=[CH:5]2
Reactant: OB(O)c1ccc2cc(O)ccc2c1
Reactant: O=C(O)c1cnc(Cl)nc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cnc(-c2ccc3cc(O)ccc3c2)nc1
Temperature: 120 °C

Procedure:
Followed procedure described in Step 1 of Example 7 starting from 6-hydroxynaphthalen-2-ylboronic acid and 2-chloropyrimidine-5-carboxylic acid with modifications: the solvent was dioxane/water (6/1), and the reaction was heated to 120° C. by microwave for 0.5 h. Purified by prep-HPLC. 1H-NMR (DMSO-d6 500 MHz): 13.70 (brs, 1H), 10.12 (s, 1H), 9.29 (s, 2H), 8.97 (s, 1H), 8.42-8.44 (d, J=9.0 Hz, 1H), 8.00-8.01 (d, J=8.5 Hz, 1H), 7.82-7.84 (d, J=9.0 Hz, 1H), 7.20 (s, 1H), 7.15-7.18 (dd, J=2.0, 9.0 Hz, 2H). MS (ESI): m/z=267.0 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.Br[CH:12]([CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].O1CCC(C=CC(OCC)=O)CC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:12]([CH2:18][CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Brc1cccc2[nH]ncc12
Reactant: CCOC(=O)C(Br)CC1CCOCC1
Agent: CCOC(=O)C=CC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CCOCC1)n1ncc2c(Br)cccc21
Yield: 53.4 %

Procedure:
A mixture of 4-bromo-1H-indazole (3.00 g), a 1:1 mixture (6.73 g) of ethyl 2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate and ethyl 3-(tetrahydro-2H-pyran-4-yl)-2-propenoate, potassium carbonate (2.1 g) and N,N-dimethylformamide (20 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (3.10 g) as a yellow oil from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). MS: 383 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Br.Br[CH2:20][CH2:21][CH2:22][NH2:23].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:8][N:9]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: NCCCBr
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1(c2ccccc2)CCN(CCCN)CC1
Yield: 63.6 %

Procedure:
A mixture of 4-ethoxycarbonyl-4-phenylpiperidine (30.5 g, 0.131 mol), 3-bromopropylamine hydrobromide (42.93 g, 0.196 mol), potassium carbonate (36.14 g, 0.241 mole), and KI (10.8 g, 0.065 mol) in 1,4-dioxane (500 mL) was stirred and refluxed for 24 hours. Dioxane was evaporated at reduced pressure, the residue was treated with ice-cold 6N NaOH (400 mL) and extracted with CH2Cl2 (4×120 mL). Solvent was evaporated from the combined dried (K2CO3) CH2Cl2 extracts and the residue was purified by column chromatography on silica gel using CHCl3 /MeOH/2M NH3 in MeOH (20:2:1) as the eluent to afford the product as a viscous oil (24.2 g, 83.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28]C[CH2:26][CH2:25][CH2:24]3)[CH2:14]OCC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[C:42]([F:44])[C:41]([OH:45])=[C:40]([F:46])[CH:39]=1.[C:48]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:49]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:39]=[C:40]([F:46])[C:41]([O:45][CH2:14][CH:13]([N:12]2[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:23]2[CH2:24][CH2:25][CH2:26][CH2:49][CH2:48][CH2:28]2)=[C:42]([F:44])[CH:43]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Reactant: COC(=O)c1cc(F)c(O)c(F)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1cc(F)c(OCC(C2CCCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cycloheptyl-ethanol (Example 1, intermediate c), 3,5-difluoro-4-hydroxy-benzoic acid methyl ester (commercially available), triphenylphosphine and di-tert-butyl azodicarboxylate. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Colorless solid. MS (Turbo Spray): 575.4 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[OH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=1
Reactant: OCCN1CCOCC1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1cc(OCCN2CCOCC2)ncn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 321.4 %

Procedure:
A mixture of 4,6-dichloropyrimidine (1.0 g, 6.7 mmol), N-(2-hydroxyethyl)morpholine (0.79 g, 0.60 mmol), and potassium carbonate (2.8 g, 20 mmol) in acetonitrile (5 mL) was stirred at room temperature for 15 h. The solvent was removed in vacuo and the residue was purified on a silica gel column using a gradient dichloromethane/methanol, (100:1 to 2:1), as the eluent to give 0.47 g (32% yield) of the yellow title compound: 1H NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 6.72 (s, 1H), 4.45 (t, J=6 Hz, 2H), 3.62 (m, 4H), 2.46 (m, 4H) 2.69 (t, J=6 Hz, 2H), 13C NMR (CDCl3, 100 MHz) δ 169.9, 160.5, 157.9, 107.8, 66.7, 64.4; MS (ESP) m/z 244 (M++1).
Reaction SMILES: [Cl:1][CH:2]=[C:3]1[C:7]([CH2:9][CH3:10])([CH3:8])[CH2:6][CH2:5][O:4]1.[ClH:11]>>[Cl:1][CH2:2][C:3](=[O:4])[C:7]([CH2:9][CH3:10])([CH3:8])[CH2:6][CH2:5][Cl:11]
Reactant: Cl
Reactant: CCC1(C)CCOC1=CCl
Product: CCC(C)(CCCl)C(=O)CCl
Reaction time: 2 h
Yield: 81 %

Procedure:
64 g (0.4 mole) of 2-chloromethylene-3-ethyl-3-methyl-tetrahydrofuran are saturated with hydrogen chloride gas at 10° to 20° C., while cooling with ice. After the mixture has been left to stand at room temperature for 2 hours, excess hydrogen chloride is stripped off and the residue is distilled. 60 g (81% of theory) of 1,5-dichloro-3-ethyl-3-methyl-2-pentanone of boiling point 92°-101° C./0.05 mbar are obtained. ##STR102##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>[Pd].C1COCC1.CCO.CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CCC(=O)Nc2ccccc2C(=O)O)cc1OC
Reaction time: 16 h
Yield: 78.9 %

Procedure:
Palladium on carbon (5%, 50 mg) was added to a solution of (E)-2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (tranilast) (0.50 g, 1.5 mmol) in THF (9.0 mL), EtOH (1.0 mL) and AcOH (1 drop). The suspension was stirred under an atmosphere of hydrogen for 16 h and filtered. The filtrate was concentrated under reduced pressure and the crude product was recrystallised from EtOAc/petrol to give 2-[[3-(3,4-dimethoxyphenyl)-1-oxopropyl]amino]benzoic acid (0.39 g, 77%) as a colourless crystalline solid; mp 137° C., lit. [24] 136-137.5° C.; δH (500 MHz, DMSO-d6) 2.68 (t, J=7.5 Hz, 2H, CH2CO), 2.87 (t, J=7.5 Hz, 2H, CH2Ar), 3.68 (s, 3H, OCH3), 3.70 (5, 3H, OCH3), 6.74 (d, J5′,6′=8.2 Hz, 1H, H6′), 6.82 (d, J5′,6′=8.2 Hz, 1H, H5′), 6.86 (s, 1H, H2′), 7.12 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.57 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.95 (d, J3,4=8.0 Hz, 1H, H3), 8.47 (d, J5,6=8.0 Hz, 1H, H6), 11.11 (s, 1H, NH), 13.57 (br s, 1H, CO2H).
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:40])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][N:28]([C:37](=[O:39])[CH3:38])[O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:24][CH2:23]2)[CH:17]([CH:41]([OH:43])[CH3:42])[C:16]3=[O:44])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:49].O>[Pd].O1CCOCC1>[Na+:49].[C:37]([N:28]([CH2:27][CH:25]1[O:24][CH2:23][CH:22]([S:21][C:20]2[CH:19]([CH3:40])[CH:18]3[N:15]([C:16](=[O:44])[CH:17]3[CH:41]([OH:43])[CH3:42])[C:14]=2[C:12]([O-:13])=[O:11])[CH2:26]1)[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)N(CC1CC(SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)C(C(C)O)C3C2C)CO1)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N(CC1CC(SC2=C(C(=O)[O-])N3C(=O)C(C(C)O)C3C2C)CO1)OCc1ccccc1

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.272 gof product from Example 74, 0.0402 g of sodium bicarbonate, 2 ml of water, 11.3 ml of dioxane, and 0.110 g of 10% palladium/carbon to give 0.059 g ofthe desired product.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].OC(C(F)(F)F)=O.[NH2:38][CH2:39][C:40]([CH3:45])([CH3:44])[C:41]([OH:43])=[O:42].C[O-].[Na+]>CCO>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=3)=[N:6][C:5]([C:3]([NH:38][CH2:39][C:40]([CH3:45])([CH3:44])[C:41]([OH:43])=[O:42])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(CNC(=O)c1nc(-c2cncc(F)c2)c2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 140 °C
Yield: 34 %

Procedure:
A mixture of 7-benzyl-1-(5-fluoro-pyridin-3-yl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (17 mg, 0.042 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (39 mg, 0.17 mmol), and NaOMe (18 mg, 0.34 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc/CH2Cl2+1% AcOH). The product was then dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 7 mg of the title compound. MS: (+) m/z 491.37 (M+1).
Reaction SMILES: O[CH2:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH2:4][NH:5][C:6](=[O:12])[O:7]C(C)(C)C.[Cl:23]S([N:27]=C=O)(=O)=O.O.C(=O)(O)[O-].[Na+]>C(#N)C>[ClH:23].[NH2:27][CH2:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH2:4][NH:5][C:6](=[O:12])[OH:7]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(CO)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cl
Product: NCC(CNC(=O)O)c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A solution of 350 mg (1.10 mmol) of the compound of Example 17A in 50 ml of acetonitrile was cooled to −15° C., and a solution of 191 μl (2.19 mmol) of chlorosulphonyl isocyanate in 10 ml of acetonitrile was added dropwise. After 5 min, 50 ml of water were added and the mixture was heated at 60° C. for 4 h. After cooling to RT, 50 ml of a saturated aqueous sodium bicarbonate solution were added and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the volatile components on a rotary evaporator. 5 ml of a 4 N solution of hydrogen chloride in dioxane were added to the residue, and the mixture was stirred for 5 min Once more, the volatile components were then removed on a rotary evaporator. The residue (385 mg) corresponded to the crude title compound in a purity of about 60% according to LC/MS (about 70% of theory); this material was reacted further without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:8][CH:9]=1
Reactant: O=C1COCCN1c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2.6 g 4-(4-Nitro-phenyl)-morpholin-3-one in 350 ml ethyl acetate and 17 ml ethanol, 13.2 g SnCl2 dihydrate were added and the reaction mixture was heated to reflux for 2 h. Then after cooling to RT the mixture was stirred for 16 h. The precipitated product was collected by filtration and was pure enough for the next reaction step. Yield: 2.07 g.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[C:10](=O)(O)[O-:11]>CO>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([O:11][CH3:10])[N:1]=1
Reactant: O=C([O-])O
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CO
Product: COc1nc(Cl)nc(Cl)n1

Procedure:
Cyanuric chloride was reacted with methanol in the presence of bicarbonate at 30° C. as described in the literature to give the product: mp 89-91° C. (lit mp 87-89° C., J. R. Dudley, et al, J. Amer. Chem. Soc., 1951, 73, 2986-2990), after recrystallization from heptane. 1H-NMR (CDCl3): δ4.12 (OCH3).