Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:15][OH:16])[CH:3]=[CH:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[C:17]([NH:34][C@H:35]([C:39](O)=[O:40])[CH:36]([CH3:38])[CH3:37])([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:17]([NH:34][C@H:35]([C:39]([O:16][CH2:15][CH:2]([OH:1])[CH:3]=[CH:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])=[O:40])[CH:36]([CH3:37])[CH3:38])([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(C=CC(O)CO)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(O)C=CC(=O)OCc1ccccc1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl 4,5-dihydroxy-2-pentenoate (4.4 g, 20 mmole), N-FMOC-L-valine (5.8 g, 17 mmole) and DMAP (0.21 g, 1,7 mmole) in 100 ml dichloromethane was cooled to about 10° C. A solution of DCC (4.2 g, 20 mmole) in 25 ml dichloromethane was added dropwise at the same temperature and the mixture was stirred overnight at room temperature. The mixture was cooled to 5° C. and the urethane was filtered. The filtrate was evaporated under reduced pressure and the product was isolated by silica gel column chromatography.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:9]([O:11]CC)=O.CC[O-].[Na+].[N:23]1([C:29]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36](=[O:41])[CH2:35][CH2:34]3)=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:9]([N:26]1[CH2:27][CH2:28][N:23]([C:29]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36](=[O:41])[CH2:35][CH2:34]3)=[O:30])[CH2:24][CH2:25]1)=[O:11]
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: CCOC(=O)c1ccc(OC)c(OC)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Yield: 6.5 %

Procedure:
To 100 ml of ethanol was added 1.9 g of ethyl 3,4-dimethoxybenzoate, 0.5 g sodium ethylate and 2.4 g of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril, the mixture was reacted in an autoclave under 110 atmospheric pressure at 140°-150° C. for 6 hours. After the reaction was completed, the reaction mixture was cooled and concentrated under a reduced pressure. The residue thus obtained was dissolved in 200 ml of chloroform and the chloroform solution was washed with 1%-potassium carbonate aqueous solution, a dilute hydrochloric acid and water in this order, then dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was treated by means of a silica gel column chromatography (Silica gel: Wako C-200, eluent: chloroform:methanol (volume/volume)=20:1) and the crude crystals were recrystallized from ethanol-chloroform to obtain 250 mg of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:16][F:17])([CH3:15])[C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[Br:18]Br>C(Cl)Cl>[F:1][CH2:2][C:3]([CH2:16][F:17])([CH3:15])[C:4](=[O:14])[CH:5]([Br:18])[O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: CC(CF)(CF)C(=O)COc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClCCl
Product: CC(CF)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1
Yield: 89 %

Procedure:
166 g (0.632 mol) of 3,3-bisfluoromethyl-1-(4-chlorophenoxy)-butan-2-one were dissolved in 500 ml of methylene chloride, and 100 g (0.625 mol) of bromine were added dropwise at 20° to 30° C., while stirring and cooling. The mixture was subsequently stirred at 20° C. for 2 hours. After distilling off the solvent in vacuo, the residue was crystallized from petroleum ether. 190 g (88% of theory) of 3,3-bisfluoromethyl-1-bromo-1-(4-chlorophenoxy)-butan-2-one of melting point 54°-55° C. were obtained. ##STR75##
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)#[N:2].O.[CH3:13]O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C#N)nc1
Reaction time: 0.17 h

Procedure:
6-Cyanonicotinic acid (500 mg) was dissolved in dichloromethane (25 ml), water-soluble carbodiimide (776 mg), methanol (0.164 ml) and 4-dimethylaminopyridine (49 mg) were added thereto, and the mixture was stirred for 2 hr 10 min. The reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 2 L, elution solvent: hexane/ethyl acetate) to give the title compound. The same reactions were repeated using 6-cyanonicotinic acid (547 mg) to give the title compound (total 951 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:22]([O:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1)(=[O:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 50 °C

Procedure:
20.0 g (75% pure, 42.5 mmol) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate were added to a suspension of 16.3 g (84.9 mmol) of cesium acetate in 80 ml of DMF. The resulting mixture was heated at 50° C. for 1.5 h. After cooling, the mixture was diluted with ethyl acetate, washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1→about 10:1). This gave 11.7 g (76.4% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si](CC)(CC)CC)[CH2:16]I)=[CH:11][C:10]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(P(N(C)C)(N(C)C)=O)C.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][NH2:31])=[CH:11][C:10]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of N-{2-benzyloxy-5-(2-iodo-(1R)-1-[(triethylsilyl)oxy]-ethyl)-phenyl}-methanesulfonamide (EP 0 659 737) (4.48 g, 8 mmol) and sodium azide (0.65 g, 10 mmol) in 100 mL of HMPA was stirred at 60° C. overnight. After cooling to room temperature the mixture was diluted with diethyl ether, washed with water, dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. The residue was dissolved in 200 mL of THF/H2O (10:1) and triphenylphosphine (2.62 g, 10 mmol) was added. After overnight stirring at room temperature, the solvents were removed and the residue was partitioned between ethyl acetate and water. The organic layers were combined and dried over MgSO4 and concentrated. The residue was redissolved in 100 mL of THF and tetrabutylammonium fluoride (TBAF) (10 mL, 1 M solution in THF) was added. The reaction was stirred for 2 hours then the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using triethylamine-methanol-CH2Cl2 (1:1:3) to give the title compound as white solid; MS (ES) m/z: 337.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:22]([O:24]C)=[O:23])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([N+:19]([O-])=O)[CH:13]=2)=[CH:4][C:3]=1[F:27].C(O)(=O)C.ClC(Cl)C>CO.[Pd]>[NH2:19][C:14]1[CH:13]=[C:12]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:27])=[C:2]([Cl:1])[N:11]=3)[C:6](=[O:26])[C:7]([C:22]([OH:24])=[O:23])=[CH:8]2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: COC(=O)c1cn(-c2ccc(F)c([N+](=O)[O-])c2)c2nc(Cl)c(F)cc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(Cl)Cl
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Methyl 7-chloro-6-fluoro-1-(4-fluoro-3-nitrophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (600 mg) was dissolved in 30 ml of methanol, 10 ml of acetic acid and 30 ml of dichloroethane, and 100 mg of 10% palladium on carbon was added thereto. Under a hydrogen atmosphere, the solution was stirred at room temperature overnight. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. To the residue were added 4 ml of acetic acid and 1 ml of hydrochloric acid. The solution was heated and stirred at 100° C. overnight. The reaction solution was concentrated in vacua. Diethyl ether was added to the residue whereupon the solid was collected by filtration and washed with diethyl ether to give 160 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:19]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:17]=[CH:16][C:12]=2[C:13]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COc1ccc(-c2cc(-c3ccc(F)cc3)ccc2C(=O)O)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(-c3ccc(F)cc3)ccc2C(=O)N2CCOCC2)cc1OC
Temperature: 20 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
2-(3,4-Dimethoxyphenyl)-4-(4-fluorophenyl)-benzoic acid (compound 204 1.6 g; 0.00454 mole), tetrahydrofuran (50 ml) and diimidazolecarbonyl (0.92 g; 0.0057 mole) are introduced into a 100 ml flask. The mixture is stirred at 20° C. for 2 hours. Morpholine (1 ml; 0.0113 mole) is then added and the mixture is maintained under stirring for six hours. The reaction mixture is poured into distilled water (150 ml) and the precipitate is filtered, washed with water (100 ml) and then dried in the air. 2-(3,4-Dimethoxyphenyl)-4-(4-fluorophenyl)-1-morpholinocarbonylbenzene (1.3 g; yield: 68.4%) in thus obtained in the form of a white solid of m.p. 153° C. (compound 201).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:26][O:27][CH2:28][CH:29]1[CH2:34][NH:33][CH2:32][CH2:31][N:30]1[CH3:35].C(N(C(C)C)CC)(C)C>C(#N)C>[C@H:15]1([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]4[CH2:32][CH2:31][N:30]([CH3:35])[CH:29]([CH2:28][O:27][CH3:26])[CH2:34]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: COCC1CNCCN1C
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCC1CN(CC(=O)Nc2ccc3c(c2)COC(N[C@@H]2CCc4ccccc42)=N3)CCN1C

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3, step A) (70 mg, 0.197 mmol), commercially available rac-2-methoxymethyl-1-methyl-piperazine (CAS no. 734507-92-7) (28.5 mg, 0.197 mmol) and diisopropylethyl amine (167 ul, 0.984 mmol) in acetonitrile (2 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a light yellow (50 mg, 55%), MS (ISP) m/e=464.3 [(M+H)+].
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]([F:22])[F:21]>CN(C=O)C>[F:21][CH:20]([F:22])[CH2:19][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1]
Reactant: FC(F)CBr
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCC(F)F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
10.04 g of isovanillin and 15.5 g of potassium carbonate are placed in an autoclave. 50 ml of DMF are added as well as 12.44 g of 2-bromo-1,1-difluoroethane. The autoclave is closed and heated at 60° C. for 20 h. Then the solids are filtered off and washed with 120 ml of DMF. About 120 ml of the solvent are distilled off and the residue poured on 200 ml of ice/water, where the product precipitates. After stirring the slurry for 30 minutes the product is filtered off and dried to give 13.69 g of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[CH:10]=[CH:11][CH:12]([OH:39])[CH2:13][O:14][C:15](=[O:38])[C@H:16]([CH:35]([CH3:37])[CH3:36])[NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:47](Cl)(=[O:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64].C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9](=[O:40])[CH:10]=[CH:11][CH:12]([O:39][C:47](=[O:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:13][O:14][C:15](=[O:38])[C@H:16]([CH:35]([CH3:37])[CH3:36])[NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(O)C=CC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OC(C=CC(=O)OCc1ccccc1)COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 8 h

Procedure:
To a solution of benzyl-5-(N-FMOC-L-valyloxy)-4-hydroxy-2-pentenoate (6.5 g, 12 mmol) and pyridine (2.0 g, 25 mmole) in 100 ml dichloromethane at 10° C. was added dropwise a solution of stearoylchloride (4.55 g, 15 mmol) in 25 ml dichloromethane. The mixture was stirred overnight. 100 ml of 5% sodium hydrogencarbonate solution was added and the mixture was stirred for 30 minutes. The organic phase was seperated and the water phase was extracted two times with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The product was isolated by silica gel column chromatography Yield: 7.8 g=80%
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[C:13]3[S:19][C:18]([C:20](O)=[O:21])=[CH:17][C:14]=3[NH:15][N:16]=1)=[CH:6]2.ON1C2C=CC=CC=2N=N1.N=C=N.[CH2:36]([O:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH3:37].C(O)C(N)(CO)CO>ClCCl.CO.CN(C)C=O>[CH2:36]([O:38][CH2:39][CH2:40][CH2:41][NH:42][C:20]([C:18]1[S:19][C:13]2[C:12]([C:7]3[NH:8][C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([CH2:2][OH:1])=[CH:11][CH:10]=4)=[N:16][NH:15][C:14]=2[CH:17]=1)=[O:21])[CH3:37]
Reactant: CCOCCCN
Reactant: O=C(O)c1cc2[nH]nc(-c3cc4cc(CO)ccc4[nH]3)c2s1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CCOCCCNC(=O)c1cc2[nH]nc(-c3cc4cc(CO)ccc4[nH]3)c2s1
Reaction time: 4 h
Yield: 17.3 %

Procedure:
To a mixture of 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid [159 mg, 0.507 mmol, Example 37], 1-hydroxybenzotriazole (116 mg, 0.858 mmol), PS-carbodiimide (1.2 mmol/g, 845 mg) in Dichioromethane (8 mL) and dimethyl formamide (2 mL) is stirred at room temperature for 25 minutes before addition of 3-ethoxypropylamine (45 mg, 0.436 mmol). After 4 h, PS-trisamine (4.03 mmol/g, 500 mg) is added and stirred for 6 hours. The reaction mixture is filtered and the resin washed under suction with Dichloromethane (3×15 mL). The filtrate is evaporated in vacuo. The crude is purified by chromatography on 10 g silica gel cartridge (ethyl acetate then 1% methanol in ethyl acetate) to give thick semi solid. It is redissolved in methanol and triturated with water to give 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid (3-ethoxy-propyl)-amide [30 mg, Example 39] as pale yellow solid; 1H NMR [(CD3)2SO)]: δ 13.490 (1H, s, NH), 11.56 (1H, NH, s), 8.70 (1H, t), 7.88 (1H, s), 7.51 (1H, s), 7.38 (1H, d), 7.10 (1H, s), 6.66 (1H, s), 5.01 (1H, t, OH), 4.55 (2H, HOCH2—), 3.44 (6H, m), 1.80 (2H), 1.12 (3H, t); LC/MS: 399 (M+H).
Reaction SMILES: C[N:2]([CH3:8])C(N(C)C)=N.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].CC(C)(O)C#N>C(#N)C>[CH3:17][O:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][CH:20]=[C:11]([CH2:10][C:8]#[N:2])[CH:12]=1
Reactant: CN(C)C(=N)N(C)C
Reactant: COC(=O)c1cccc(CBr)c1
Agent: CC(C)(O)C#N
Solvent: CC#N
Product: COC(=O)c1cccc(CC#N)c1
Reaction time: 72 h

Procedure:
1,1,3,3-Tetramethylguanidine (3.21 ml, 25.6 mmol) was added dropwise to a solution of methyl 3-bromomethylbenzoate (2.80 g, 12.2 mmol) and acetone cyanohydrin (1.59 ml, 18.3 mmol) in acetonitrile (40 ml) at room temperature. The reaction was stirred for 3 days and the solvent then removed under reduced pressure. The resulting brown oil was purified by column chromatography on silica gel using ethyl acetate:pentane (50:50) as eluant to afford the title compound as a clear oil, 1.80 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[N:17]([CH:18]=2)[N:16]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[S:14]3)=[CH:7][CH:6]=1)C.[C:27](=[O:30])([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[N:17]([CH:18]=2)[N:16]=[C:15]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:30][CH3:27])=[CH:23][CH:24]=2)[S:14]3)=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2cn3nc(-c4ccc(O)cc4)sc3n2)cc1
Reactant: O=C([O-])[O-]
Reactant: BrCCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)OC)cc4)nc3s2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 4-[2-(4-hydroxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester (1 g) and potassium carbonate (4 g) in N,N-dimethylformamide (50 ml) was added 1,5-dibromopentane (2 ml) and the mixture was stirred at room temperature for 6 hours. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration, washed with water and methanol. To a suspension of the powder in methanol (10 ml) was added sodium methylate (28% in methanol) (20 ml) and the mixture was stirred at 80° C. for 19 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration, washed with water, methanol and diisopropyl ether and dried to give 4-[2-[4-(5-methoxypentyloxy)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid methyl ester (479 mg).
Reaction SMILES: [Br:1][C:2]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([Cl:19])[C:13]=1[Cl:20].C([N:23](CC)CC)C>O1CCCC1>[Br:1][C:2]1([C:8]([C:12]2[C:17]([NH2:23])=[CH:16][C:15]([OH:18])=[C:14]([Cl:19])[C:13]=2[Cl:20])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Nc1ccc(O)c(Cl)c1Cl
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C1(Br)CCCCC1
Solvent: C1CCOC1
Product: Nc1cc(O)c(Cl)c(Cl)c1C(=O)C1(Br)CCCCC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 64.8 %

Procedure:
12.6 g (0.056 mol) of 1-bromo-cyclohexanecarboxylic acid chloride are added dropwise at 0° C. with stirring to a mixture of 10 g (0.056 mol) of 4-amino-2,3-dichlorophenol and 100 ml of tetrahydrofuran. After adding half (5 g) of the acid chloride, 7.7 ml (0.05 mol) of triethylamine are added dropwise at the same time. When the addition has ended, the reaction mixture is stirred for 24 hours at 20° C. and then poured into 300 ml of ice-water. The mixture is extracted twice using in each case 300 ml of dichloromethane, and the organic phase is dried over magnesium sulphate and evaporated by stripping off the solvent under reduced pressure. The residue which remains is recrystallized from toluene. In this manner. 11.9 g (58% of theory) of 4-(1-bromo-cyclohexanoyl)-amino-2,3-dichloro-phenol are obtained in the form of a solid substance of melting point 142° C.
Reaction SMILES: ClCCl.C([O:11][C:12]1[CH:13]=[C:14]([C:18]2[C:23]([CH3:24])=[C:22]([C:25]#[N:26])[C:21]([NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:20]([O:34]C)[C:19]=2[Br:36])[CH:15]=[CH:16][CH:17]=1)C1C=CC=CC=1.BrB(Br)Br.O>[Cl-].[Na+].O>[Br:36][C:19]1[C:20]([OH:34])=[C:21]([NH:27][C:28](=[O:33])[C:29]([CH3:31])([CH3:32])[CH3:30])[C:22]([C:25]#[N:26])=[C:23]([CH3:24])[C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([OH:11])[CH:13]=1
Reactant: COc1c(Br)c(-c2cccc(OCc3ccccc3)c2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(C#N)c(NC(=O)C(C)(C)C)c(O)c(Br)c1-c1cccc(O)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
A dichloromethane (18 ml) solution of N-(3′-benzyloxy-2-bromo-5-cyano-3-methoxy-6-methylbiphenyl-4-yl)-2,2-dimethylpropionamide (I-13) (620 mg, 1.22 mmol) was cooled at −78° C., a dichloromethane solution of 1 N tribromoborane (3.67 ml, 3.67 mmol) was dropwise added, followed by stirring at −78° C. for 20 minutes. Afterwards, this was heated up to −12° C. and stirred for 1 hour, then heated up to 0° C. and stirred for 30 minutes. The reaction liquid was put into cold water (50 ml), saturated brine (50 ml) was added, the intended product was extracted with ethyl acetate (70 ml×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the entitled compound (457 mg, 96%) as a yellow white semi-solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCCC2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCCC2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.5 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(1-piperidinylcarbonyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 14) (334 mg, 0.77 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound as a beige solid (266 mg).