Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:10])=O)[S:4][N:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([Cl:13])=[O:10])[S:4][N:3]=1
Reactant: O=C(O)c1snc(Cl)c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1snc(Cl)c1Cl

Procedure:
After thionyl chloride (10 ml) had been added to 3,4-dichloro-5-isothiazole-carboxylic acid (1.28 g), the mixture was refluxed by heating for 2 hours. The excess of thionylchloride was then distilled off under reduced pressure, and 3,4-dichloro-5-isothiazolecarboxylic acid chloride was obtained.
Reaction SMILES: C([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[F:20])C1C=CC=CC=1.CO.[H][H]>[C].[Pd].C(OCC)(=O)C>[F:20][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([O:18][CH3:19])[C:9]=1[OH:8])[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: COc1cc(C(=O)O)cc(F)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)O)cc(F)c1O

Procedure:
To 4-benzyloxy-3-fluoro-5-methoxybenzoic acid were added 20 ml of methanol, 20 ml of ethyl acetate and 50 mg of 10% palladium-carbon, and the mixture was stirred at room temperature for 4 hours under the hydrogen atmosphere. Thereafter, the reaction mixture was filtered through Celite (registered trade mark). The filtrate was concentrated under reduced pressure, and 4.5 g of 3-fluoro-4-hydroxy-5-methoxybenzoic acid was obtained.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6].[CH3:9][C:10]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:11][CH2:12][CH2:13][CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[CH3:9][C:10]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:11][CH2:12][CH2:13][CH2:14][O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]
Reactant: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Reactant: OCC(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=CCCCOCC(O)CO)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
0.26 g (55%, 5.9 mmol) of sodium hydride was added to a solution of 0.54 g (5.9 mmol) of glycerol in dry N,N-dimethylformamide (6 mL) with cooling on ice. After the mixture was stirred for 30 min at 50° C., the above (5,9,13-trimethyltetradec-4-enyl)tosylate was added dropwise, with additional stirring for 18 hours at the same temperature. After addition of water at 0° C., the reaction mixture was extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 73 mg of the title compound (6% yield in 2 steps). The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:21]Cl>O1CCCC1.CN(C)C=O>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:21][S:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1S
Reactant: ClCOc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1SCOc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A solution of 28 g (0.25 mol) of potassium tert.-butylate in 120 ml of tetrahydrofuran was slowly added dropwise to a solution of 33.6 g (0.2 mol) of methyl 2-mercapto-benzoate in 50 ml of tetrahydrofuran at 5° C. At the end of the dropwise addition, stirring was continued at 5° C. for a further 30 minutes. The solid product precipitated was filtered off with suction and dissolved in 100 ml of dimethylformamide. A solution of 42.3 g (0.2 mol) of chloromethyl 2,4-dichlorophenyl ether in 60 ml of dimethylformamide was added dropwise to this solution, while stirring at 25° C. The mixture was subsequently stirred at 30° C. for 1 hour and then worked up by stirring into 1.5 liters of ice-water. The suspension thereby formed was filtered off with suction and the solid product precipitated was dried in air. 62 g (90.4% of theory) of 1-(2,4-dichlorophenoxy)-1 -(2-methoxycarbonyl-phenylthio)-methane were obtained in this manner in the form of colourless crystals of melting point 122°-124° C.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]2[O:24][C:25]3[CH:31]=[C:30]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:28][C:26]=3[N:27]=2)[CH:17]=1>>[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]2[O:24][C:25]3[CH:31]=[C:30]([CH2:32][C:33]([NH:14][C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:15])[CH:13]=4)=[O:34])[CH:29]=[CH:28][C:26]=3[N:27]=2)[CH:17]=1
Reactant: COC(=O)CCCOc1cccc(N)c1
Reactant: O=C(O)Cc1ccc2nc(Nc3cccnc3)oc2c1
Product: O=C(O)CCCOc1cccc(NC(=O)Cc2ccc3nc(Nc4cccnc4)oc3c2)c1

Procedure:
Methyl4-(5-aminophenoxy)butyrate was made as described in example 7 above and coupled with 2-(3-pyridylamino)-6-carboxymethylbenzoxazole according to the method described in example 7 to produce the methyl ester of 2-(3-pyridylamino)-6-{3-[3-carboxypropoxy]anilinocarbonyl methyl}benzoxazole
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=2[C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:10])=[O:9])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[C:37]([F:38])[CH:36]=3)=[CH:23][C:24]=2[C:25]2[CH:29]=[N:28][NH:27][CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2cn[nH]c2)cc1F
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3ccc(F)c(F)c3)cc2-c2cn[nH]c2)cc1F
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
15.0 mg (0.03 mmol) of 5-chloro-4-((6-chloro-4-(1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide was dissolved in 1.5 mL of 1,4-dioxane, and 7.1 mg (0.05 mmol) of (3,4-difluorophenyl)boronic acid was added thereto, and then 3.5 mg (10 mol %) of Pd(PPh3)4, 12.4 mg (0.09 mmol) of K2CO3, and 0.3 mL of H2O were added thereto. After reacting with microwave reactor at 150° C. for 30 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, dimethylchloride:methanol=20:1) to obtain 9.0 mg (31.9% yield) of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][C:22](=[O:28])[NH:23]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)(C)C>[N:11]1([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][C:22](=[O:28])[NH:23]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=C1CCc2c(cccc2OCCCN2CCN(Cc3ccccc3)CC2)N1
Reactant: [H][H]
Solvent: CC(C)O
Product: O=C1CCc2c(cccc2OCCCN2CCNCC2)N1

Procedure:
(a)-2 5 Grams of 5-[3-(4-benzylpiperazinyl)propoxy]-3,4-dihydrocarbostyril and 0.8 g of 5%-Pd charcoal are added into 150 ml of isopropanol and catalytically reduced at 60° C. for 5 hours under 3 atm. of hydrogen gas pressure. The catalyst is removed by filtration and the mother liquor thus obtained is concentrated under reduced pressure. The residue is recrystallized from ligroin-benzene to obtain 4.1 g of 5-(3-piperazinylpropoxy)-3,4-dihydrocarbostyril in the form of colorless prism-like crystals having a melting point of 195°-196° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[N:13]=[C:14]([CH2:17]Br)[S:15][CH:16]=1)=[O:11])[CH3:8].[I:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>CC(C)=O>[CH2:7]([O:9][C:10]([C:12]1[N:13]=[C:14]([CH2:17][O:26][C:23]2[CH:24]=[CH:25][C:20]([I:19])=[CH:21][CH:22]=2)[S:15][CH:16]=1)=[O:11])[CH3:8]
Reactant: Oc1ccc(I)cc1
Reactant: CCOC(=O)c1csc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Yield: 57.6 %

Procedure:
Ground potassium carbonate (3.4 g, 24.6 mmol) was added to a solution of 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (12.83 g, 56 mmol; from Step 1 above) and 4-iodophenol (5.5 g, 25 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.) in acetone (440 mL). The reaction mixture was heated at reflux for 15 h and then it was filtered and water was added to the filtrate until it turned cloudy. The filtrate was left on ice and then the resulting white solid was filtered off, washed with acetone/hexanes (2:1) and dried to give 2-(4-iodo-phenoxymethyl) -thiazole-4-carboxylic acid ethyl ester (5.6 g, 65%) as a white solid. 1HNMR (CDCl3): δ 1.4 (t, 3H, J=7 Hz), 4.46 (q, 2H, J=7 Hz), 5.4 (s, 2H), 6.7 (d, 2H, J=9 Hz), 7.6 (d, 2H, J=9 Hz), 8.2 (s, 1H).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].CO[C:8]1[CH:13]=[CH:12][C:11]([N:14]=[N:15][C:16]2[N:20]([CH3:21])[CH:19]=[CH:18][N+:17]=2[CH3:22])=[CH:10][CH:9]=1.[NH2:23][C:24]1[CH:28]=[CH:27][NH:26][N:25]=1>CC(O)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[NH2:23][C:24]1[CH:28]=[CH:27][N:26]([C:8]2[CH:13]=[CH:12][C:11]([N:14]=[N:15][C:16]3[N:20]([CH3:21])[CH:19]=[CH:18][N+:17]=3[CH3:22])=[CH:10][CH:9]=2)[N:25]=1
Reactant: COc1ccc(N=Nc2n(C)cc[n+]2C)cc1
Reactant: Nc1cc[nH]n1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)O
Product: Cn1cc[n+](C)c1N=Nc1ccc(-n2ccc(N)n2)cc1
Reaction time: 3 h

Procedure:
2.5 g (7.6 mmol) of 2-(4-methoxyphenylazo)-1,3-dimethyl-3H-imidazol-1-ium perchlorate and 50 ml of 2-propanol are charged to a fully equipped round-bottomed flask. The mixture is brought to 60° C. 1.3 g (15.5 mmol) of 3-aminopyrazole are added. This mixture is brought, with stirring, to the reflux temperature of the solvent for 3 hours.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[C:16]1([N:22]2[C:34]3[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][C:5]3[CH:14]=[CH:15][C:2]([C:31]4[CH:32]=[CH:33][C:34]5[N:22]([C:16]6[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=6)[C:23]6[C:28]([C:29]=5[CH:30]=4)=[CH:27][CH:26]=[CH:25][CH:24]=6)=[CH:3][C:4]=3[C:8]=2[CH:9]=1
Reactant: Brc1ccc2oc3ccc(Br)cc3c2c1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc2oc3ccc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3c2c1
Temperature: 90 °C
Yield: 55 %

Procedure:
A mixture of 2,8-dibromodibenzo[b,d]furan (2.868 g, 10 mmol), (9-phenyl-9H-carbazol-3-yl)boronic acid (3.26 g, 10 mmol), Pd(PPh3)4 (0.30 g, 0.26 mmol) and potassium carbonate (4.1 g, 30 mmol) in dioxane/water (50 mL/10 mL) was degassed and heated at about 90° C. overnight. The resulting mixture was worked up with ethyl acetate/brine, dried over Na2SO4, purified by flash column (hexanes to hexanes/ethyl acetate 40:1). The desired fraction was collected and concentrated, filtration and dried in air to give a white solid (2.70 g, in 55% yield).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[N:9][N:10]([C@H:11]([CH2:16][O:17][CH3:18])[CH2:12][CH2:13][O:14][CH3:15])[C:6]=2[CH:5]=[C:4]([CH3:19])[N:3]=1.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([Br:30])[CH:29]=1)[NH:26][CH2:25][CH2:24]2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O>C1COCC1>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([Br:30])[CH:29]=1)[N:26]([C:2]1[C:7]3[N:8]=[N:9][N:10]([C@H:11]([CH2:16][O:17][CH3:18])[CH2:12][CH2:13][O:14][CH3:15])[C:6]=3[CH:5]=[C:4]([CH3:19])[N:3]=1)[CH2:25][CH2:24]2
Reactant: COCC[C@@H](COC)n1nnc2c(Cl)nc(C)cc21
Reactant: Brc1cc(Br)c2c(c1)CCN2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC[C@@H](COC)n1nnc2c(N3CCc4cc(Br)cc(Br)c43)nc(C)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.5 %

Procedure:
(S)-4-chloro-1-(1-methoxymethyl-3-methoxypropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine (0.72 g, 2.54 mmol) and 5,7-dibromoindoline (0.72 g, 2.60 mmol) were dissolved in anhydrous THF (6 mL) and cooled in an ice bath. To that a 1 M solution of NaHMDS in THF (3.0 mL, 3.0 mmol) was added and the reaction was stirred for 20 min, allowed to warm to 25° C. and stirred for 3 h. Then water (30 mL) was added and the mixture was extracted twice with EtOAc (80 and 40 mL). The combined organic extracts was washed with brine (30 mL) dried (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel using 40% EtOAc/hexanes as eluent to give the product (1.14 g, 85% yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17][CH2:16][C:4]21[CH2:8][N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:5]2.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:9]([N:7]1[CH2:6][CH2:5][C:4]2([CH2:16][CH2:17][CH2:18][NH:19][CH:3]2[CH2:2][NH2:1])[CH2:8]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1NCCCC12CCN(Cc1ccccc1)C2
Temperature: 25 °C

Procedure:
1 mmol of tert-butyl 6-aminomethyl-2-benzyl-2,7-diazaspiro[4.5]decane-7-carboxylate is dissolved in 2 ml of dichloromethane and the solution is admixed with 2 ml of trifluoroacetic acid. The reaction solution is stirred at room temperature until conversion is complete and then is poured into saturated aqueous sodium hydrogen carbonate solution. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: Cl.C([N:9]1[C:17]2[N:16]3[N:18]=[C:19]([CH3:30])[C:20]([C:21]4[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=4[CH3:29])=[C:15]3[N:14]=[C:13]([CH3:31])[C:12]=2[CH2:11][CH2:10]1)C1C=CC=CC=1.O.C(O)C>[H][H].[C].[Pd]>[C:26]1([CH3:27])[CH:25]=[C:24]([CH3:28])[CH:23]=[C:22]([CH3:29])[C:21]=1[C:20]1[C:19]([CH3:30])=[N:18][N:16]2[C:17]3[NH:9][CH2:10][CH2:11][C:12]=3[C:13]([CH3:31])=[N:14][C:15]=12
Reactant: [H][H]
Reactant: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCN4Cc2ccccc2)c(C)c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCN4)c(C)c1
Yield: 71.6 %

Procedure:
Concentrated hydrochloric acid (1 mL) was added to a mixture of 8-benzyl-3-mesityl-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (4.7 g) which is a free compound of the compound prepared in Example 26, water-containing 5% palladium carbon (3.0 g) and ethanol (300 mL), followed by stirring at room temperature for two days in hydrogen atmosphere. After filtering through Celite, the filtrate was evaporated, which was neutralized with an aqueous solution of sodium bicarbonate. The resulting solid was filtered, and dissolved in a mixed solution of dichloromethane, methanol and ethyl acetate. After filtering off the insoluble matter, the mixture was purified by silica gel column chromatography (10-67% ethyl acetate/hexane), to give the title compound as white crystals (2.6 g). 1.0 g of a raw material was recovered.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([OH:12])[CH2:11][O:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]([F:20])([F:19])[CH2:17][OH:18].CC(C)([O-])C.[K+]>CN(C=O)C>[OH:12][C:8]1([C:7]2[C:2]([O:18][CH2:17][C:16]([F:20])([F:19])[F:15])=[CH:3][C:4]([C:13]#[N:14])=[N:5][CH:6]=2)[CH2:11][O:10][CH2:9]1
Reactant: N#Cc1cc(Cl)c(C2(O)COC2)cn1
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(OCC(F)(F)F)c(C2(O)COC2)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
To a solution of 4-chloro-5-(3-hydroxyoxetan-3-yl)pyridine-2-carbonitrile (example 123b, 1 g, 4.75 mmol) in dry DMF (20 ml) under an argon atmosphere cooled down to 0° C. was added 2,2,2-trifluoroethanol (570 mg, 412 μl, 5.7 mmol) followed by addition of potassium tert-butoxide (639 mg, 5.7 mmol). The reaction was stirred at 0° C. for 10 minutes and then stirred at 80° C. for 2 hours. DMF was removed in vacuo and the residue was dissolved in ethylacetate. The organic phase was extracted with a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase back-extracted with ethylacetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (1.2 gr, 92%); MS (ESI, m/z): 275.4 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>Cl>[N:8]([C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 4-nitroaniline (27.6 g) in 0.4N hydrochloric acid (500 ml) was added 1M aqueous sodium nitrite solution (200 ml) under ice-cooling, and the mixture was stirred for 30 min and then at room temperature for 20 min. An aqueous solution (100 ml) of sodium azide (13.0 g) was added to the obtained reaction mixture under ice-cooling, and the mixture was stirred for 30 min. The precipitated crystals were collected by filtration, washed with 1N hydrochloric acid and water and air-dried to give the title compound as a brown powder (28.2 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH3:34][O:35][CH2:36][CH2:37][NH2:38].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:24])[NH:38][CH2:37][CH2:36][O:35][CH3:34])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NCCOC
Yield: 72.5 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (68c) (112 mg, 0.22 mmol), methoxyethylamine (40 μL, 0.46 mmol), WSC hydrochloride (130 mg, 0.68 mmol) and HOBT (30 mg, 0.22 mmol), to obtain 88.8 mg of the title compound as a white solid (71%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][N:12]1[C:16]([CH3:17])=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][N:12]1[C:16]([CH3:17])=[C:15]([C:2]2[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=2)[CH:7]=[O:8])[CH:14]=[N:13]1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(F)c(C=O)c2)cnn1C
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (200 mg, 0.99 mmol) in DMF (5 mL) and H2O (1 mL) are added 1,5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (328 mg, 1.5 mmol), Pd(PPh3)4 (113 mg, 0.099 mmol) and K2CO3 (204 mg, 1.5 mmol) at room temperature. The solution is heated to 100° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and is filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×10 mL). The combined organic layer is dried with MgSO4 (500 mg) and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash chromatography with 20% EtOAc in Hepthane as the eluent to afford 5-(1,5-dimethyl-1H-pyrazol-4-yl)-2-fluoro-benzaldehyde (160 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][C:7]([Br:11])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.FC1C=CC(CCN2CCC(=[O:28])CC2)=CC=1>>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][C:7]([Br:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:28]
Reactant: CC1(C)CNc2cc(Br)ccc21
Reactant: O=C1CCN(CCc2ccc(F)cc2)CC1
Product: CC1(C)C(=O)Nc2cc(Br)ccc21
Yield: 89.2 %

Procedure:
3,3-Dimethyl-6-bromoindoline (3.10 g), 1-[2-(4-fluorophenyl)ethyl]-4-piperidone (2.81 g) and triacetoxylated sodium borohydride (5.70 g) were treated as in Example 16 to give the title compound (2.72 g) as a white amorphous solid (yield: 49.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=2)=[N:6]1.[N:31]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:40]([O:39][C:37]([N:31]1[CH2:36][CH2:35][N:34]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:4][C:3]3[C:26]([Cl:30])=[CH:27][CH:28]=[CH:29][C:2]=3[Cl:1])[N:6]=[C:7]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=3)[CH:8]=2)[CH2:33][CH2:32]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3c(Cl)cccc3Cl)n2)ccc1F
Product: Cc1cc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(Cc3c(Cl)cccc3Cl)n2)ccc1F
Yield: 90.8 %

Procedure:
Following the procedure of Example 1(10), 2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 90.8%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@@H:4]([O:24][CH2:25][CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][C:7]=1[C:20]([F:23])([F:22])[F:21]>[Pd]>[CH3:1][O:2][C:3](=[O:27])[C@@H:4]([O:24][CH2:25][CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[C:20]([F:23])([F:21])[F:22]
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1C(F)(F)F)C(=O)OC
Agent: [Pd]
Product: CCO[C@@H](Cc1ccc(O)cc1C(F)(F)F)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 d], (2S)-3-(4-benzyloxy-2-trifluoromethyl-phenyl)-2-ethoxy-propionic acid methyl ester was hydrogenated over 10% palladium on charcoal to give (2S)-2-ethoxy-3-(4-hydroxy-2-trifluoromethyl-phenyl)-propionic acid methyl ester as yellow solid.