Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(C1C=CC(OC)=C(C=1)[CH:31]=[O:32])C(F)(F)F>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:17])([F:18])[F:1])=[CH:10][C:11]=1[CH:31]=[O:32]
Reactant: COc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C=O
Product: COc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1C=O

Procedure:
This compound was prepared from Compound 99 in the same manner of Compound 9.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O-:12].[Na+]>CN(C)C=O.CO.[Cu]Br>[CH3:11][O:12][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: C[O-]
Agent: [Cu]Br
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cnc2[nH]ccc2c1

Procedure:
Under an argon atmosphere and in an anhydrous medium, 1 g (5.07 mmol) of the compound obtained in Step C is dissolved in a mixture of 25 ml of N,N-dimethylformamide and 22 ml of methanol; 6.86 g (126.75 mmol) of sodium methanolate and 1.43 g (10.30 mmol) of copper(I) bromide are added at room temperature. The mixture is heated at reflux for 3 hours. After removal of the solvents by evaporation, the residue is taken up in water and ethyl acetate and then filtered over Celite. The organic phase is washed with water, dried over magnesium sulphate and evaporated to yield a solid, which is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 7:3). The title compound is obtained in the form of a brown solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=2)[C:5]#[N:6])=[CH:14][CH:13]=1
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(CNc2cc(C#N)ccn2)cc1
Temperature: 25 °C

Procedure:
To pyridine (500 mL) were added 2-chloroisonicotinonitrile (22.0 g, 159 mmole), para-methoxybenzylamine (25 g, 114% Meq.), and NaHCO3 (30 g). The mixture was heated under reflux overnight. After cooling to RT, the mixture was filtered and the filter cake was rinsed with CH2Cl2. The combined filtrate was concentrated to dryness in vacuum to form a yellow solid. This solid is then recrystallized in EtOAc to give a light yellow crystalline compound and the mother liquor was concentrated and subjected to EtOAc again (repeating three times) to yield the desired compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([Sn](C)(C)C)=[N:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:14][CH:13]=1)[CH3:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]2[N:44]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:45](I)=[N:46][C:40]=2[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C1(C)C=CC=CC=1.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]2[N:44]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:45]([C:16]3[C:15]4[C:19](=[CH:20][C:12]([C:4]5[CH:5]=[C:6]([F:11])[C:7]([O:9][CH3:10])=[CH:8][C:3]=5[CH2:1][CH3:2])=[CH:13][CH:14]=4)[N:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:17]=3)=[N:46][C:40]=2[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc(I)n2COCC[Si](C)(C)C)C1
Reactant: CCc1cc(OC)c(F)cc1-c1ccc2c([Sn](C)(C)C)nn(C3CCCCO3)c2c1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1cc(OC)c(F)cc1-c1ccc2c(-c3nc4c(n3COCC[Si](C)(C)C)CCN(C(=O)OC(C)(C)C)C4)nn(C3CCCCO3)c2c1
Temperature: 100 °C
Yield: 74.2 %

Procedure:
To a solution of 6-(2-ethyl-5-fluoro-4-methoxy-phenyl)-1-(tetrahydro-pyran-2-yl)-3-trimethylstannanyl-1H-indazole (Preparation 18, 735 mg, 1.53 mmol) in toluene (6 mL) was added 2-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (Preparation 22, 805 mg, 1.68 mmol), copper (1) iodide (60 mg, 310 μmol) and tetrakis(triphenylphosphine) palladium(0) (173 mg, 150 μmol). The reaction mixture was degassed with nitrogen, heated at 100° C. for 18 hours, cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 20% EtOAc in toluene to give the title compound as a foam (801 mg) in a 74% yield.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C(O[CH:22](OCC)[CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])C>C(#N)C.C(O)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOC(CCNC(=O)OC(C)(C)C)OCC
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOCc1nc2cnc3ccccc3c2n1N=CCCNC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 99.9 %

Procedure:
A solution of 2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (1.00 g, 4.13 mmol) in 20 mL of acetonitrile and 5 mL of glacial acetic acid was treated with tert-butyl (3,3-diethoxypropyl)carbamate (2.55 g, 10.3 mmol) and heated to reflux under an atmosphere of nitrogen. After 15 h, the reaction mixture was concentrated under reduced pressure to yield a brown oil. The oil was partitioned between CHCl3 and saturated NaHCO3 solution and the phases were separated. The organic portion was washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl {3-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)imino]propyl}carbamate (1.64 g) as a dark red/orange oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[C:4]2[N:9]([C:10]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2>ClCCl.CO>[Cl:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[C:4]2[N:9]([C:10]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: COC(=O)c1c(Cl)c(-c2cccnc2)n2c1CCCC2
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1c(Cl)c(-c2cccnc2)n2c1CCCC2
Yield: 84.1 %

Procedure:
2-Chloro-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid is prepared as in Example 44, from 0.9 g of methyl 2-chloro-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate. 0.72 g of 2-chloro-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid are thus obtained in the form of a white powder (Rf=0.43; thin layer chromatography on silica gel; eluent: 9/1 dichloromethane/methanol).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C=O)C>[CH2:18]([NH:25][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1NCc1ccccc1
Temperature: 80 °C

Procedure:
To a stirring solution of 0.81 g (3.0 mmol) of the above 2-chloro-3-nitro-5-trifluoromethyl-benzoic acid in 6.0 mL of DMF was added 6.0 mL of TEA, followed by 3.0 mmol of Benzylamine. The mixture was heated at 80° C. for 6 h. After cooling to r.t., 3.0 mL of 6N HCl solution was added. The solid was collected, washed with fresh water to give 2-benzylamino-3-nitro-5-trifluoromethyl-benzoic acid. LCMS: 341 (M+1)+. This product was hydrogenated according to the general procedure C to give 0.25 g of 2,3-diamino-5-trifluoromethyl-benzoic acid. LCMS: 221 (M+1)+.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].Br[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O>[CH2:1]([O:5][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][C:3]#[CH:4]
Reactant: BrCCCCc1ccccc1
Reactant: C#CCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCCOCCCCc1ccccc1
Reaction time: 72 h
Yield: 66.7 %

Procedure:
A mixture of 3-butyn-1-ol (5.0 g), (4-bromobutyl)benzene (15.0 g), aqueous sodium hydroxide (30 ml, 50% w/v), and TAB (0.6 g) was stirred vigorously for 3 days, treated with water (100 ml) and extracted with ER (2×200 ml). The dried extract was evaporated and the residue was purified by FCC eluting with CX-ER 19:1 to give the title compound as a colourless oil (9.5 g). T.l.c. (CX-ER 9:1) Rf 0.45.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=O)=[CH:4][N:3]=1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=[N:12][OH:13])=[CH:4][N:3]=1
Reactant: Cc1ncc(C=O)c(N)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ncc(C=NO)c(N)n1
Reaction time: 4 h
Yield: 78.1 %

Procedure:
To 8.6 g of 2-methyl-4-amino-5-formylpyrimidine, while stirring at room temperature in a mixture of 272 ml of methanol and 68 ml of water, was added dropwise 10 ml of an aqueous solution containing 5.1 g of hydroxylamine hydrochloride. The reaction was allowed to proceed for further 4 hours at room temperature. To the reaction solution was added dropwise 30 ml of an aqueous solution containing 3.90 g of sodium carbonate to cause precipitation of crystals. The crystals were collected by filtration and dried under reduced pressure to give 7.45 g (yield 78.2%) of 2-methyl-4-amino-5-pyrimidine aldoxime. The mother liquor was subjected to quantitative determination (by absolute calibration curve method) of 2-methyl-4-amino-5-pyrimidine aldoxime by means of high performance liquid chromatography to confirm that 1.95 g (yield 20.5%) of the object compound was produced. The total yield of the crystals thus obtained and the object compound in the mother liquor was 98.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[OH:9].[H-].[Na+].[CH3:14]I>C1COCC1>[CH3:14][O:9][CH:4]1[C:3]([O:10][CH3:11])([O:2][CH3:1])[CH2:8][CH2:7][O:6][CH2:5]1
Reactant: CI
Reactant: COC1(OC)CCOCC1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1COCCC1(OC)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4,4-dimethoxytetrahydro-2H-pyran-3-ol (6.00 g, 37.0 mmol) in THF (100 mL) at 0° C. was added sodium hydride (1.48 g, 37.0 mmol). After being stirred at 0° C. for 1 h, methyl iodide (4.61 mL, 74.0 mmol) was added dropwise. The reaction was allowed to warm up to ambient temperature and quenched using aqueous NH4Cl. The product was extracted with ether three times. The combined extracts were dried over Na2SO4 and concentrated. Purification by flash chromatography on silica gel (10% ether to 60% ether/hexanes) provided the desired product. 1H NMR (CDCl3) δ 4.05-3.95 (1H, m), 3.80-3.70 (1H, m), 3.60-3.50 (3H, m), 3.50 (3H, s), 3.30 (3H, s), 3.10 (3H, s), 2.00-1.70 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13](C2NC=CC=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[OH-].[Na+].CCO.S(Cl)([Cl:31])(=O)=O>>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13]([Cl:31])(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(OCc2sccc2S(=O)(=O)c2ccc[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(OCc2sccc2S(=O)(=O)Cl)cc1
Yield: 46 %

Procedure:
2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl chloride was prepared, as described in Example 64E, using N-{2-[(4-methylphenoxymethyl]thiophene-3-sulfonyl}pyrrole by basic hydrolysis (NaOH/EtOH) followed by conversion to the corresponding sulfonyl chloride, in 46% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:40][O:41][CH2:42][C:43]1[NH:44][CH:45]=[C:46]([OH:50])[C:47](=[O:49])[N:48]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][CH2:42][C:43]2[NH:44][CH:45]=[C:46]([OH:50])[C:47](=[O:49])[N:48]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCc4nc(=O)c(O)c[nH]4)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.2 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (25 mg) (0.042 mmol), 8.6 mg (0.055 mmol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 10.5 mg (0.055 mmol) of p-toluenesulphonic acid hydrate are dissolved in 3 ml of absolute dimethylacetamide. After stirring at room temperature for 24 hours the solvent is removed in a high vacuum at room temperature and the residue is treated with 3 ml of water. The precipitated product is filtered off and washed in succession with water and diethyl ether. After drying in a high vacuum there are obtained 20 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyrimidinyl)methoxy]imino]acetamido]-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl] thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:14].[F:16][C:17]([F:29])([F:28])[CH:18](OS(C(F)(F)F)(=O)=O)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][C@@H:18]([CH3:19])[C:17]([F:29])([F:28])[F:16])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:15])(=[O:12])=[O:11]
Reactant: CC(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 21.7 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid methyl ester [68029-77-6], 32.5 mmol trifluoro-methanesulfonic acid 2,2,2-trifluoro-1-methyl-ethyl ester [212556-43-9], 43.4 mmol potassium carbonate in 87 ml DMF was stirred at 80° C. for 48 hour After cooling to RT, the mixture was concentrated in vacuo, taken in water and stirred for 1 hour. Filtration yielded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13]O)[CH:7]=[CH:6]2.O=S(Cl)[Cl:17]>C(Cl)Cl>[Cl:17][CH2:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1
Reactant: COc1ccc2cc(CO)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2cc(CCl)ccc2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A cooled (0° C.) mixture of (6-methoxynaphthalen-2-yl)methanol (90 mg; 0.48 mmol) in anh. DCM (2 ml) was treated dropwise with SOCl2 (89 mg; 0.75 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 17 h. The volatiles were removed under reduced pressure, and the solid residue was triturated with Et2O. Filtration afforded 2-(chloromethyl)-6-methoxynaphthalene which was directly used for the next reaction. LC-MS (conditions E): tR=0.75 min.; no ionisation.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:8]=1
Reactant: O=C(O)c1cccc(-c2ccncc2)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a solution of 3-(pyridin-4-yl)benzoic acid (300 mg, 1.5 mmol) in DCM (6 mL) was added EDCI (430 mg, 2.20 mmol), HOBt (296 mg, 2.20 mmol), Et3N (556 mg, 4.50 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (370 mg, 1.80 mmol). The mixture was stirred at room temperature for 16 h, then the reaction mixture was washed with water and extracted with DCM. The organic layer was then dried, concentrated and the residue purified by prep-HPLC to give the title product (230 mg, Yield 40%). 1H NMR (400 MHz, MeOD) δ 8.54 (d, J=4.0 Hz, 2H), 8.16 (s, 1H), 7.85-7.80 (m, 2H), 7.64 (dd J=4.0 Hz, 2H), 7.48 (dd, J=7.6 Hz, 1H), 7.03-6.95 (m, 4H), 4.13 (br.s, 1H), 3.66 (s, 2H), 3.60-3.48 (m, 2H), 2.80-2.77 (m, 4H), 2.63-2.59 (m, 2H). LCMS (m/z): 388.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.CN1CCN(C)[C:16]1=[O:21].C[O-].[Na+]>CO>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[O:21][CH3:16]
Reactant: CN1CCN(C)C1=O
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)nc2c(O)cccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-chloro-8-hydroxy-2-methylquinoline (9 g), 1,3-dimethyl-2-imidazolidinone (100 ml) and 28% solution of sodium methoxide in methanol (135 ml) was stirred at 150°0 C. for 4 hours. The reaction mixture was cooled to ambient temperature followed by partition into ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The crystalline residue was washed with n-hexane to give 8-hydroxy-4-methoxy-2-methylquinoline (5.57 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].Cl.[CH3:37][NH2:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32]([NH:38][CH3:37])[C:27]=2[S:26][CH:25]=1)=[O:23]
Reactant: CN
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Agent: Cl
Product: CNc1ncnc2c(C(=O)Nc3cc(C(=O)Nc4cccc(C(F)(F)F)c4)ccc3C)csc12

Procedure:
The procedure of Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and methylamine hydrochloride to obtain the title compound (see Table 1).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:8])=[O:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C(=O)C(O)c2ccccc2)cc1

Procedure:
Compounds of the invention having the formula ##STR26## can be prepared as follows. Benzaldehyde and 4-methoxybenzaldehyde are reacted to yield 4-methoxybenzoin, which is converted to the hemisuccinate by reaction with succinic anhydride. The latter is reacted with urea and acetic acid to yield the intermediate 4-(4-methoxyphenyl)-5-phenyl-2-oxazole-propionic acid. ##STR27## The latter intermediate is demethylated with hydrogen bromide and esterified with methanol to yield the corresponding hydroxy methyl ester intermediate, which is then reacted with an appropriate haloalkyl-A compound, where A is as defined hereinbefore and hal is halo, to yield the desired final product as the methyl ester. ##STR28## The ester can be hydrolyzed by conventional methods to yield the desired final product in its free carboxylic acid form.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH2:19])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:27]([C:24]3[CH:23]=[CH:22][C:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)(=[O:29])=[O:28])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCCC2N
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)COc1cccc2c1CCCC2NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (5-amino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (199 mg, 0.72 mmol) and biphenyl-4-sulfonyl chloride (217 mg, 0.86 mmol) in dry tetrahydrofuran (10 mL) was added diisopropylethylamine (186 mg, 1.44 mmol) at 0° C. The reaction mixture was stirred at room temperature for 12 hours, and then concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, and evaporated in vacuo. Column chromatography (silica gel, 100-200 mesh, 10-15% ethyl acetate in hexane) gave [5-(biphenyl-4-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester. MS cald. for C28H31NO5S 493, obsd. 494 [(M+H)+].
Reaction SMILES: C(O[CH:5]1[C:10]2=[CH:11][C:12]3[C:17]([N:9]2[CH2:8][CH2:7][CH:6]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)(=O)C.CN(C)C(N(C)C)=N>C1(C)C=CC=CC=1>[CH:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[C:10]1[CH:5]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][CH2:8][N:9]12
Reactant: CCOC(=O)C1CCn2c(cc3ccccc32)C1OC(C)=O
Agent: CN(C)C(=N)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc3ccccc3n2CC1
Temperature: 80 °C
Yield: 83.4 %

Procedure:
A solution of 9.93 g (0.033 mol) of ethyl 9-acetoxy-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylate in 150 ml of toluene is treated with 8.3 ml (0.066 mol) of 1,1,3,3-tetra-methylguanidine and the reaction mixture is heated at 80° C. for 17 hours. The resulting solution is then cooled to room temperature, washed in succession three times with 50 ml of 1N hydrochloric acid each time, 50 ml of aqueous sodium bicarbonate solution and 50 ml of sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. After trituration of the residue with n-hexane, there are obtained 6.64 g (83%) of ethyl 6,7-dihydropyrido[1,2-a]indole-8-carboxylate as a pale yellow solid, m.p. 77°-79° C.