Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:3]=1[NH2:4].[Br:11]Br>C(O)(=O)C>[BrH:11].[Br:11][C:7]1[CH:6]=[C:5]([O:9][CH3:10])[C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: COc1cccc(F)c1N
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: COc1cc(Br)cc(F)c1N
Temperature: 5 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 2-fluoro-6-methoxyaniline (1 equiv) in acetic acid (0.7 M) was cooled to 5° C. A mixture of bromine (0.9 equiv) in acetic acid (0.7 M) was slowly added. The reaction mixture was stirred for 2 h at 5° C. The resulting solid was filtered, washed with ether, and dried to give the title compound (90% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.84 (s, 3H) 6.79 (br. s., 2H) 6.97 (s, 1H) 7.06 (d, J=10.09 Hz, 1H). MS (ESI) m/z 219.9 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])C(OCC)=O.[C:21](=[O:24])([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([O:18][C:16](=[O:17])[CH:10]([O:24][C:21]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[CH3:20]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(I)c1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cccc(I)c1)Oc1cccc(I)c1
Yield: 17.2 %

Procedure:
A stirred solution of 40.0 g (0.18 mol) of 3-iodophenol, 33.6 ml (0.18 mol) of diethyl bromomalonate and 27.63 g (0.2 moles) of milled anhydrous potassium carbonate in 250 ml dry N,N-dimethylformamide was heated at 110°-120° C. under argon for 14 hours. The mixture was cooled and concentrated in vacuo. The resulting residue was combined with 600 ml of ice-cold water and the oily product was extracted with ethyl acetate (4×150 ml). The combined ethyl acetate extracts were dried (MgSO4) and concentrated in vacuo to an orange oil. The orange oil was purified by chromatography (eluted by 5% methylene chloride in hexanes to 50% methylene chloride in hexanes) to yield 8.1 g (8.5%) of the desired product as a tan oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]1C(C(O)=O)=CC=[CH:7][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:24][C@@H:25]([C:28]([N:30]1[C@H:34]([C:35]([OH:37])=[O:36])[CH2:33][CH2:32][CH2:31]1)=[O:29])[CH2:26][SH:27].[CH2:38]1[CH2:42][O:41][CH2:40][CH2:39]1>>[Cl:1][CH2:2][C:3]1[CH:40]=[CH:39][C:38]([C:42]([S:27][CH2:26][C@@H:25]([CH3:24])[C:28]([N:30]2[CH2:31][CH2:32][CH2:33][C@H:34]2[C:35]([OH:37])=[O:36])=[O:29])=[O:41])=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccccc1CCl
Reactant: C1CCOC1
Reactant: C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: C[C@H](CSC(=O)c1ccc(CCl)cc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
α-chloro-toluic acid (9.0 g, 0.0528 Mol) and carbonyldiimidazole (10.3 g, 0.0634 Mol) were dissolved in THF (100 ml) and stirred overnight at room temperature. Then TEA was added (7.4 ml. 0.0528 Mol) and to this reaction mixture a solution of captopril (11.5 g, 0.0528 Mol) in THF (20 ml) was added dropwise and the reaction was stirred overnight at room temperature. The mixture was then partitioned between KHSO4 10% and EtOAc (120 ml). The organic layer was separated and the aqueous phase was extracted with EtOAc (2×60 ml). The combined organic phases were washed with water (3×60 ml), dried over sodium sulphate and evaporated under reduced pressure affording 14.1 g of 1-[(2S)-3-(4-chloromethylbenzoyl)mercapto-2-methyl-1-oxopropyl]-L-proline as a white solid used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:24][N:25]=1)[NH:6]2.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][N:25]=1)[NH:6]2
Reactant: CCOC(=O)CC1CN=C(c2cc3c(C)ccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc12
Temperature: 25 °C
Yield: 107.3 %

Procedure:
Ethyl (2-{4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.99 g) was dissolved in a mixed solvent of tetrahydrofuran (12 mL)-methanol (12 mL), and the mixture was ice-cooled. Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (0.35 g) in water (5 mL)) was added to this solution, and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (1.00 g, yield: 95%) as pale-yellow crystals. MS: 450 (MH+). melting point 269-270° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O=[C:17]1[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:18]1>N1C=CC=CC=1>[C:27]1([C:19]2[CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[N:18]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1cc(-c2ccccc2)[nH]c(=O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc(-c2ccccc2)c1
Reaction time: 0.17 h

Procedure:
With cooling with ice, trifluoromethanesulfonic acid anhydride (3.7 mL) was added to a pyridine (80 mL) solution of methyl 2-oxo-6-phenyl-1,2-dihydropyridine-4-carboxylate (2.8 g), and this was stirred for 10 minutes with cooling with ice, and then at room temperature for 2 hours. With further cooling with ice, trifluoromethanesulfonic acid anhydride (1 mL) was added to it, stirred at that temperature for 5 minutes and then overnight at room temperature. The reaction liquid was concentrated under reduced pressure, then ethyl acetate was added thereto, and the formed precipitate was taken away through filtration. Water was added to the filtrate, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline water. This was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[C:24]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:23]=[CH:22][N:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[CH:25]=[C:24]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:23]=[CH:22][N:21]=1)=[O:19]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C(=O)CBr)c1
Product: CCOC(=O)n1c(C(=O)c2cc(CO[Si](C)(C)C(C)(C)C)ccn2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromoacetyl-4-[(tert-butyldimethylsilyloxy)methyl]pyridine (step 4).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9](Cl)[N:8]=[C:7]([Cl:12])[N:6]=2)[CH2:3][CH2:2]1.O1CCOCC1.[NH3:19]>CCOCC>[CH:1]1([NH:4][C:5]2[N:6]=[C:7]([Cl:12])[N:8]=[C:9]([NH2:19])[N:10]=2)[CH2:2][CH2:3]1
Reactant: N
Reactant: Clc1nc(Cl)nc(NC2CC2)n1
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1nc(Cl)nc(NC2CC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
138 g of 2-cyclopropylamino-4,6-dichloro-s-triazine are added at a slightly elevated tmeperature and with vigorous stirring to a mixture of 675 ml of dioxane and 135 ml of ether. After cooling to room temperature, 101 ml of 25%, aqueous ammonia are added dropwise over a period of 20 minutes. The reaction mixture is heated to 50° C., stirred for 16 hours and then concentrated by evaporation under water jet vaccum. The dry riesidue is diluted with 500 ml. of water and after stirring for 1 hour at room temperature, the tiny white crystals formed are separated by filtering under suction and dried under water jet vacuum at 80° C. 217 g. of 2-cyclopropylamino-4-chloro-6-amino-s-triazine are obtained.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH3:12]OC(OC)OC>S(=O)(=O)(O)O.CO>[CH3:12][NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1
Reactant: COC(OC)OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CNc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Yield: 79.6 %

Procedure:
A mixture of 4-trifluoromethylaniline (6.7 g), trimethylorthoformate (6.6 g) and sulfuric acid (0.22 g) was heated at 90° C. and the methanol formed in the reaction was allowed to distill off. Additional trimethylorthoformate (4 mL) was added twice more. After each addition the reaction mixture was distilled. A final aliquot trimethylorthoformate (5 mL) was added and the reaction mixture was heated at 150° C. for four hours. The reaction mixture was cooled and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was removed, dried over sodium sulfate, and concentrated to a yellow oil. This oil was then suspended in 2N aqueous HCl (100 mL) and then heated at 80° C. for eight hours. The reaction mixture was then cooled, made basic to pH 11 with aqueous NaOH, and extracted with ether. The organic layer was dried over magnesium sulfate and concentrated to an oil. This oil was further purified by chromatography on silica gel (350 g, elute with hexane:ether (60/40)) to give 5.8 g of N-methyl-4-trifluoromethylaniline as a low-melting solid. Condensation of N-methyl-4-trifluoromethylaniline with cyanoacetic acid, as described in Preparation 1 yielded 6.0 g of α-cyano-N-methyl-4-trifluoromethylacetanilide; m.p. 68°-70° C.
Reaction SMILES: [C:1]([CH2:3][O:4]C(CCNC1C=CC=C(C)C=1)=O)#[N:2].CO.S(=O)(=O)(O)N.[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[N:34][C:35]2[CH:51]=[CH:50][C:38]([N:39]([CH2:48][CH3:49])[CH2:40][CH2:41][C:42](OCC#N)=[O:43])=[CH:37][C:36]=2[CH3:52])=[CH:29][CH:28]=1)([O-:26])=[O:25]>CC(C)=O.O>[N+:24]([C:27]1[CH:28]=[CH:29][C:30]([N:33]=[N:34][C:35]2[CH:51]=[CH:50][C:38]([N:39]([CH2:48][CH3:49])[CH2:40][C:41](=[C:42]=[O:43])[O:4][CH2:3][C:1]#[N:2])=[CH:37][C:36]=2[CH3:52])=[CH:31][CH:32]=1)([O-:26])=[O:25]
Reactant: Cc1cccc(NCCC(=O)OCC#N)c1
Reactant: CCN(CCC(=O)OCC#N)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)c(C)c1
Agent: NS(=O)(=O)O
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: CCN(CC(=C=O)OCC#N)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)c(C)c1

Procedure:
The diazo solution obtained was added gradually to a stirred coupling mixture of N-ethyl, N-(2-cyanomethoxycarbonylethyl)-m-toluidine (7.3 parts), methanol (50 parts), water (200 parts) and sulphamic acid (1 part). After two hours the product was isolated by filtration, washed with cold water and dried to yield, 4-(4-nitrophenylazo)-3-methyl-N-ethyl-N-(2-cyanomethoxycarbonylethyl)aniline (6.5 parts) λmax=486 nm (acetone).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH3:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:24][CH2:25][C:26]#[N:27])=[CH:5][C:4]=2[N:3]=1.[OH-:28].[Na+].OO>CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH3:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:24][CH2:25][C:26]([NH2:27])=[O:28])=[CH:5][C:4]=2[N:3]=1
Reactant: [OH-]
Reactant: CCc1nc2c(N)nc3cc(CCC#N)ccc3c2n1CC1CCOCC1
Agent: OO
Agent: [Na+]
Solvent: CO
Product: CCc1nc2c(N)nc3cc(CCC(N)=O)ccc3c2n1CC1CCOCC1
Temperature: 50 °C
Yield: 27.8 %

Procedure:
3-[4-Amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanenitrile (590 mg, 1.6 mmol), 10% aqueous sodium hydroxide (132 mg, 0.33 mmol), and 30% aqueous hydrogen peroxide (516 mg, 4.55 mmol) were combined in methanol (75 mL) and the reaction was heated at 50° C. for 18 hours. The mixture was concentrated under reduced pressure and then partitioned between chloroform (75 mL) and water (75 mL). The fractions were separated and the aqueous fraction was extracted with chloroform (3×25 mL). The combined organic fractions were sequentially dried (MgSO4), filtered, concentrated to dryness and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 2 L of 10% methanol in dichloromethane). A final recrystallization from acetonitrile provided 35 mg of 3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanamide as an off-white solid, mp 197-199° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH3:35]>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:29]2[CH:30]=[CH:31][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:27][CH:28]=2)=[O:7])[C@H:9]([C:16]([NH2:35])=[O:18])[CH2:10]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: N
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(N)=O)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method-as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and ammonia (0.5M in dioxane), the title compound was obtained in 88% purity by HPLC. MS(ESI+): m/z=352.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[I:14]I.C(O)(=O)C.S(=O)(=O)(O)O>C(OC(C)C)(=O)C.O>[I:14][C:11]1[S:10][C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:13][CH:12]=1
Reactant: Fc1ccc(Cc2cccs2)cc1
Reactant: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)C
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc(Cc2ccc(I)s2)cc1
Temperature: 40 °C

Procedure:
A mixture of 2-(4-fluorophenylmethyl)thiophene (15 g, 78 mmol), prepared as in step 1, HIO3 (2.8 g, 16 mmol), I2 (7.9 g, 1.2 mmol), acetic acid (36 mL), concentrated sulfuric acid (1.2 mL), and H2O (9 mL) was heated at 40° C. for 2 hours at which point all starting material was consumed by GC analysis. The reaction mixture was cooled to ambient temperature and H2O (150 mL) and isopropyl acetate (150 mL) were added. The aqueous layer was separated, neutralized with saturated aqueous K2CO3, and extracted with isopropyl acetate (100 mL). The organic layers were combined and washed with H2O (100 mL), saturated aqueous NaHCO3 (2×100 mL), and saturated aqueous Na2S2O3 (2×100 mL). The organic phase was then treated with activated carbon, dried over MgSO4, filtered, and concentrated in vacuo to give a quantitative yield of 2-iodo-5-(4-fluorophenylmethyl)thiophene as a solution in isopropyl acetate, which is used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([C:43]([CH:40]2[CH2:42][CH2:41]2)=[O:44])[C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2ccccc2n1C(=O)C1CC1
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
To a suspension of NaH (0.004 g, 0.18 mmol) in DMF (5 mL) was added 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1H-indole-2-carboxylic acid ethyl ester (0.05 g, 0.095 mmol), obtained in step (vi) of Example 1, at 0° C., and stirred for 15 min. Cyclopropanecarbonyl chloride (0.012 g, 0.11 mmol) was added to this at the same temperature and the reaction was stirred for 6 h. The aqueous layer was extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 15% ethyl acetate and petroleum ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-cyclopropanecarbonyl-1H-indole-2-carboxylic acid ethyl ester (0.04 g, yield: 71%).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([S:25]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)(=[O:27])=[O:26])=[CH:33][CH:32]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(-c3ccccn3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(-c4ccccn4)cc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid ethyl ester (1.83 g, 3.7 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.38 g (80%); off white solid; mp 217° C.; MS: 466.9 (M+H)+
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:9](=[N:14][O:15][CH:16]=3)[C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][OH:18]>N1CCCCC1>[CH3:17][O:18][C:16]([C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][NH:11][C:10](=[O:13])[C:9]=1[NH2:14])=[O:15]
Reactant: CO
Reactant: O=c1[nH]nc(-c2ccccc2)c2conc12
Solvent: C1CCNCC1
Product: COC(=O)c1c(-c2ccccc2)n[nH]c(=O)c1N
Yield: 70 %

Procedure:
To a stirred solution of 4-phenyl-6H-isoxazolo[3,4-d]pyridazin-7-one (330 mg, 1.55 mmol) (V. Dal Piaz et al., Heterocycles, 1991, 32(6), 1173) in methanol (15 mL), piperidine was added (0.4 mL) and the mixture was refluxed for 1 h. Solvent was removed under reduced pressure and the residue was treated with water. The solid thus formed was isolated by filtration and dried to yield the title product (70% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:8][CH2:7][C:5]=2[N:6]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25]([NH:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:8][CH2:7][C:5]=2[N:6]=1)(=[O:27])=[O:26]
Reactant: CCC(=O)NC1CCc2nc(N)sc2C1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: CCC(=O)NC1CCc2nc(NS(=O)(=O)c3c(C)cc(Cl)cc3Cl)sc2C1

Procedure:
The title compound was prepared from N-(2-amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)propanamide (47 mg, 0.21 mmol) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (20.3 mg) with purity >90%. MS (pos) m/z 448.1, 450.1.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[CH:4]([O-:6])=O.[NH4+].C(O)=O.C(O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Pd].O>[CH:4]([O:3][CH2:1][CH2:2][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6]
Reactant: O=C[O-]
Reactant: CCO
Reactant: OCc1ccccc1
Agent: [Pd]
Agent: [NH4+]
Solvent: O=CO
Solvent: O
Product: O=COCCc1ccccc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 20 %

Procedure:
Pd/C (5 mol %) is weighed into a reaction flask. A solvent mixture consisting of ethanol and water (4:1) and ammonium formate (30 mol %) is added, the reaction flask is capped with a rubber septa and the mixture is heated (80° C.) for 2 minutes. Formic acid (3 equivalents) and then benzyl alcohol are added by syringe. The reaction is run for 20 minutes and the reaction is quenched with brine. The product is extracted by DCM and the organic phase is dried by Na2SO4. The product ethylbenzene was analyzed by 1H NMR and produced in 20% yield.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[S:3])[NH2:2].Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>O1CCOCC1>[C:7]([C:6]1[CH:5]=[C:4]([C:1]2[S:3][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[N:2]=2)[CH:12]=[CH:11][CH:10]=1)([OH:9])=[O:8]
Reactant: NC(=S)c1cccc(C(=O)O)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1sc(-c2cccc(C(=O)O)c2)nc1C
Temperature: 90 °C
Yield: 63.5 %

Procedure:
720 mg of 3-Thiocarbamoylbenzoic acid was suspended in 10 ml of dioxane, 720 mg of ethyl 2-chloroacetoacetate was added thereto, and the mixture was heated at 90° C. for 18 hours. After the reaction mixture was cooled, the resulting crystal was collected from the suspension by filtration and recrystallized from 20 ml of ethanol and a small amount of water to give 735 mg of ethyl 2-(3-carboxyphenyl)-4-methyl-5-thiazolecarboxylate (yield: 63%). 290 mg of the crystal was dissolved in 5 ml of 1N sodium hydroxide, and the mixture was heated at 60° C. for one hour. After the completion of the reaction, the reaction mixture was neutralized with 1N hydrochloric acid. The resulting crystal was collected by filtration and recrystallized from a 80% aqueous ethanol solution to give 258 mg of 2-(3-carboxyphenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 83%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:11][N:10]=1)(C)(C)C.[ClH:36]>CCOC(C)=O>[ClH:36].[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:23]([C:12]2[C:13]3[C:18](=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)[C:9]([CH2:8][NH2:7])=[N:10][CH:11]=2)=[O:34])=[CH:27][CH:28]=1
Reactant: COc1ccc(CNC(=O)c2cnc(CNC(=O)OC(C)(C)C)c3c(OC)cc(OC)cc23)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cnc(CN)c3c(OC)cc(OC)cc23)cc1
Yield: 54 %

Procedure:
As described in example 1, 46 mg of [6,8-dimethoxy-4-(4-methoxy-benzylcarbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 20 mg (54%) of 1-aminomethyl-6,8-dimethoxy-isoquinoline-4-carboxylic acid 4-methoxy-benzylamide hydrochloride. H1-NMR (DMSO): δ 9.26 (br s, 3H), 8.41 (s, 1H), 8.38 (br s, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.09 (s, 1H), 6.90 (d, J=8.2 Hz, 2H), 6.81 (s, 1H), 4.67 (d, J=5.1 Hz, 2H), 4.44 (d, J=5.5 Hz, 2H), 3.96 (s, 3H), 3.76 (s, 3H), 3.71 (s, 3H); MS: APCI (M+H) calc'd for C21H23N3O4+H 382.4; found 382.2.