Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:13])=[C:5]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:4]=1[CH3:20].Br[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([CH3:30])[CH:23]=1>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([N:17]2[CH2:18][CH2:19][N:14]([C:5]3[C:4]([CH3:20])=[C:3]([O:2][CH3:1])[C:11]4[O:10][CH:9]([CH3:12])[CH2:8][C:7]=4[C:6]=3[CH3:13])[CH2:15][CH2:16]2)=[CH:23][C:24]=1[CH3:30]
Reactant: COc1ccc(Br)cc1C
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Product: COc1ccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)C4)CC2)cc1C
Yield: 40.7 %

Procedure:
By using 1-(7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (552 mg, 2.0 mmol) synthesized in Reference example 88 and 4-bromo-1-methoxy-2-methylbenzene (804 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 323 mg (yield 41%). Melting point was 94 to 96° C. (ethanol-water).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1.Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])[CH2:10][C@@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccccc1F
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CN(c2ccccc2C(=O)O)CCN1C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 48 h
Yield: 55.2 %

Procedure:
To a solution of (S)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.10 g, 19.8 mmol) in pyridine (41 mL) is added 2-fluoro-benzoic acid (20.2 g. 140 mmol) followed by DBU (43 ml). The mixture is stirred at 150° C. for 48 h. The mixture is diluted with 600 mL of 2N HCl followed by extraction with EtOAc (3×300 mL). Organics are collected and purified by flash chromoatography to provide 3.50 g, 53% yield of (S)-4-(2-carboxy-phenyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:26])[C:11]([N:14]1[C:18](=[O:19])[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)S[CH2:15]1)([CH3:13])[CH3:12].ClC1C=CC=C(C(OO)=O)C=1.[S:38]([O-:42])([O-])(=[O:40])=S.[Na+].[Na+]>ClCCl.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:26])[C:11]([N:14]1[C:18](=[O:19])[CH:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:38](=[O:42])(=[O:40])[CH2:15]1)([CH3:12])[CH3:13]
Reactant: CC(C)(C(=O)Nc1cc(F)ccc1F)N1CSC(c2ccccc2)C1=O
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C(=O)Nc1cc(F)ccc1F)N1CS(=O)(=O)C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2,5-difluorophenyl)-2-(5-phenylthiazolidin-4-on-3-yl)isobutyramide (1.3 g) prepared according to Example 13 in dichloromethane (25 mL) was added portionwise 70% m-chloroperbenzoic acid (1 g) under ice-cooling, and the mixture was stirred for 30 minutes at room temperature. After adding a small amount of sodium thiosulfate, the mixture was diluted with chloroform and washed with a saturated sodium hydrogencarbonate aqueous solution. After distilling off the solvent under reduced pressure, the resulting crude product was purified by preparative thin-layer chromatography (developing solvent: chloroform/ethyl acetate=3/1) to give crystals, which were washed with a mixture of isopropyl ether-ethanol (10:1) to give 0.26 g of the title compound as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11]C)[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13]
Reactant: COc1cc(Br)c2c(c1)C(=O)NC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1NCc2c(Br)cc(O)cc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A −78° C. suspension of Example 104A (100 mg, 0.41 mmol) in dichloromethane (13 mL) was treated dropwise with 1M BBr3 in dichloromethane (1.2 mL, 1.2 mmol), stirred at −78° C. for 1 hour, and stirred at room temperature for 2 hours. The mixture was treated with additional 1M BBr3 in dichloromethnae (0.8 mL), heated to reflux overnight, then cooled to room temperature, and partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated to give 91 mg (97%) of the desired product. MS (ESI(−)) m/226, 228 (M−H)−.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:9]=2[N:10]=1)=[O:5])C.[OH-].[Na+:17]>C1COCC1>[Na+:17].[Cl:15][C:12]1[CH:13]=[CH:14][C:8]2[S:7][C:6]([C:4]([O-:5])=[O:3])=[N:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1nc2cc(Cl)ccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])c1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-chloro-benzothiazole-2-carboxylic acid ethyl ester (200 mg, 0.83 mmol) was added 3 mL of THF, and 0.83 mL (2 eq) of NaOH solution (2N in MeOH). The reaction mixture was stirred at room temperature overnight. The suspension was filtered and the solid was dried under vacuum to give 170 mg of 5-chloro-benzothiazole-2-carboxylic acid sodium salt as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[C:23](Br)[CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(O)CC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[C:23]([C:32]2[CH:31]=[N:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=2)[CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3c(Br)cccc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCO
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc23)cn1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
An argon stream is bubbled through a solution of 182 from above (500 mg, 1.2 mmol) and 2-methoxy-5-pyridine boronic acid (181 mg, 1.2 mmol) in 4 ml of 1-propanol for 15 min. Then 2M aqueous sodium carbonate solution (1.2 ml, 2.4 mmol) and bis(triphenylphosphine)palladium-(II)-chloride (50 mg, 0.07 mmol) are added and the reaction mixture is stirred at 85° C. for 3 h. Then the mixture is cooled to 0° C. and ethyl acetate and concentrated sodium hydroxide solution is added until a pH of 11 is reached. The solution is washed with brine and the organic layers are dried over sodium sulfate and evaporated. The crude product is purified by flash-chromatography (silica gel, cyclohexane/ethyl acetate 7:3).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12](C(=O)C)[CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:22]([O-])([O-:24])=[O:23].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=3)[NH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C2CN(C(C)=O)c3ccccc32)CC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: CC(=O)N1CCC(C2CNc3ccc([N+](=O)[O-])cc32)CC1
Reaction time: 72 h
Yield: 39.6 %

Procedure:
To a solution of 3-(1-acetyl-4-piperidyl)-1acetylindoline (0.3 g) in conc. sulfuric acid (5 ml) was added potassium nitrate (0.12 g) in small portions at a temperature not exceeding 10° C. with stirring. The mixture was stirred at the same temperature for 1 hour and at ambient temperature for 7 hours. The reaction mixture was poured into ice and allowed to stand at ambient temperature for 3 days. The aqueous solution was neutralized with 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel, followed by elution with a mixture of chloroform and methanol to give 3-(1-acetyl-4-piperidyl)-5-nitroindoline (0.12 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12]O)=[CH:2]1.[Na].O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH2:12])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:2]1
Reactant: ON=C(Cc1c[nH]c2ccccc12)c1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: NC(Cc1c[nH]c2ccccc12)c1ccccc1
Yield: 92 %

Procedure:
2-(1H-indol-3-yl)-1-phenylethanone-oxime (0.2 g, 0.75 mmol) dissolved in ethanol (10 ml) was mixed in portions with sodium pieces (500 mg, 21 mmol) in the boiling heat. This reaction mixture was stirred with reflux until the metal was fully dissolved. After cooling in an ice bath, water (15 ml) was carefully added to the reaction solution. The volatile constituents were then removed in a vacuum. The aqueous residue was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried with sodium sulphate, filtered and all the volatile constituents removed in a vacuum. The residue (163 mg) obtained after distilling off the solvent was purified by column chromatography [silica gel 60 (30 g); methanol (500 ml)].
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][CH2:28][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:27])[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:11])=O)(C)(C)C.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([NH:38][C:39]([N:8]1[CH2:30][CH2:29][CH2:28][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:27])[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:11])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COCc1ccccc1
Reactant: O=C=NCc1ccccc1
Product: O=C(NCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COCc1ccccc1

Procedure:
By the same procedure as in Example 21-C), while using (2S)-1-[N-(tert-butoxycarbonyl)-L-prolyl]-2-(2-benzyloxy-1-hydroxyethyl)pyrrolidine (274 mg) and benzyl isocyanate (89 μl), there was obtained 243 mg of the title compound.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[C:15]([CH3:23])=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])C=C.C(O)(=O)C.C1([SiH3])C=CC=CC=1>C(Cl)Cl.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:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[C:10]1[CH:11]=[C:12]([C:14]2[C:15]([CH3:23])=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)[S:13][C:9]=1[C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: C=CCn1ccnc1-c1sc(-c2c(C)nn3ccccc23)cc1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nn2ccccc2c1-c1cc(-c2ccc(Cl)cc2Cl)c(-c2ncc[nH]2)s1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 1-allyl-2-[3-(2,4-dichlorophenyl)-5-(tributylstannyl)-2-thienyl]-1H-imidazole (180 mg, 0.29 mmol) in DMF (4.0 mL) was added [3-bromo-2-methylpyrazolo[1,5-a]pyridine (50 mg, 0.2 mmol) (azeotroped from toluene) and Bis(triphenylphosphine)palladium(II) chloride (8.5 mg, 0.012 mmol). The resulting mixture was degassed and stirred for 1 h at 100° C. under an atmosphere of argon. The reaction mixture was allowed to cool, concentrated and the residue was partially purified by silica gel column chromatography (40 g, eluting with 30% EtOAc in hexanes to EtOAc to give 3-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl]-2-methylpyrazolo[1,5-a]pyridine, 82 mg. To a solution of [A] 3-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl]-2-methylpyrazolo[1,5-a]pyridine (70 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium(0) (8.5 mg, 0.0074 mmol) and acetic acid (0.4 mL, 7 mmol) in DCM (1.5 mL) was added slowly phenylsilane (0.1 mL, 0.8 mmol) and the reaction mixture stirred at 40° C. for 2 h. The reaction mixture was concentrated and the product was purified by column chromatography on silica gel eluting with 1-3% MeOH in DCM. The product was further purified by preparative hplc, formic acid gradient. The title compound was isolated as a colorless lyophilized solid, 25 mg. LC/MS (FA) ES+ 425.0, 427.6, 428.4, 429.3. 1H NMR (400 MHz, d4-MeOH) δ: 8.48 (d, J=8.3 Hz, 1H), 7.85-7.87 (m, 1H), 7.50-7.60 (m, 1H), 7.31-7.39 (m, 3H), 7.18 (s, 1H), 7.04 (s, 2H), 6.90-6.95 (m, 1H), 2.62 (s, 3H).
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[C:6]([O:11]C)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[N+](C1C=CC=CC=1)([O-])=O.COC1C=CC=C2C=1C=CN=N2.Br>Cl>[OH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:1]=[N:2]2
Reactant: COc1cccc2c1ccn2N
Agent: Br
Agent: COc1cccc2nnccc12
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: Oc1cccc2nnccc12
Temperature: 0 °C
Yield: 52.7 %

Procedure:
To a mixture of 4-methoxyindole (1.26 g, 8.57 mmol), powdered potassium hydroxide (10.05 g, 0.179 mol) and dry dimethylformamide (20 mL) at 15° C. under argon was added, portionwise over 0.2 h, hydroxylamine-O-sulfonic acid. Internal temperature was kept ≦30° C. by external ice bath cooling. The mixture was stirred at 20° C. for 4 h, then was extracted with toluene (4×50 mL). The combined extracts were washed with water (4×50 mL) and brine (50 mL), then dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography of the residue on silica with 5-50% ether in hexane gradient elution gave 1-amino-4-methoxyindole (0.79 g, 56%). A mixture of 1-amino-4-methoxyindole (0.78 g, 4.8 mmol), nitrobenzene (3.4 g, 27.8 mmol), and methanolic HCl (3% w/w, 180 mL) was heated at reflux for 76 h, then cooled and partitioned between 10% aqueous NaOH (50 mL) and dichloromethane (3×30 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil which was purified by chromatography on silica with 5-100% ether in hexane gradient elution. The resulting 5-methoxycinnoline (0.56 g, 3.5 mmol) was mixed with 48% aqueous HBr (35 mL) and the resulting solution heated at reflux for 18 h. The mixture was cooled, then evaporated in vacuo, and the residue dissolved in water (10 mL). Aqueous ammonia (d=0.880) was added until pH 6 was obtained, and the resulting mixture cooled to 0° C. The precipitated solid was collected by filtration and purified by charcoal-methanol treatment to give the title compound (0.37 g, 53%) as a yellow solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Br[C:17]1[CH:18]=[N:19][N:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([N:20]2[CH:21]=[C:17]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[CH:18]=[N:19]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: COc1cccc(-n2cc(Br)cn2)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-n2cc(-c3cccnc3)cn2)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 96.3 %

Procedure:
To a three-necked flask equipped with a magnetic stir bar and a condenser was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1230 mg, 6.0 mmol, 1.2 eq), Pd2(dba)3 (183 mg, 0.2 mmol, 0.04 eq) and tricyclohexylphosphine PCy3 (135 mg, 0.48 mmol, 0.096 eq). Then the flask was evacuated and backfilled with nitrogen. The evacuation and back fill procedure was repeated another two times. Then a solution of 4-bromo-1-(3-methoxyphenyl)-1H-pyrazole 3 (1266 mg, 5.0 mmol, 1.0 eq) in dioxane (25 mL) and a solution of K3PO4 (1804 mg, 8.5 mmol, 1.7 eq) in H2O (10 mL) were added by syringe independently under nitrogen. The mixture was stirred in an oil bath at a temperature of 95-105° C. for 24 hours, cooled down to ambient temperature, filtered and washed with ethyl acetate. The organic layer of the filtrate was separated, dried over sodium silphate, filtered, concentrated and the residue was purified through column chromatography on silica gel using hexane/ethyl acetate (10:1-5:1) first, then dichloromethane/methanol (10:1) as eluent to obtain the desired product 3-(1-(3-methoxyphenyl)-1H-pyrazol-4-yl)pyridine 4 as a brown solid 1.21 g in 96% yield. 1H NMR (DMSO-d6, 400 MHz): δ 3.85 (s, 3H), 6.90-6.93 (m, 1H), 7.41-7.48 (m, 4H), 8.10 (dt, J=8.0, 2.0 Hz, 1H), 8.31 (s, 1H), 8.45 (dd, J=4.8, 1.6 Hz, 1H), 8.98 (d, J=1.2 Hz, 1H), 9.13 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][OH:22])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].N1C=CN=C1>CN(C=O)C>[CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a solution of (1RS,2RS)-2-[(benzylamino)methyl]-1-(3,4-dichlorophenyl)propane-1,3-diol (3.44 g) in DMF (30 ml) were added tert-butylchlorodimethylsilane (1.68 g) and imidazole (1.03 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water, saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (2.98 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([C:10]2[S:11][C:12](I)=[CH:13][N:14]=2)([OH:9])[CH2:5][CH2:4]1)[CH3:2].[C:16]([O:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[F:33])=[O:22])([CH3:19])([CH3:18])[CH3:17].[F-].[Cs+].C(COC)OC>C(OCC)(=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.CO>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([C:10]2[S:11][C:12]([C:27]3[CH:28]=[CH:29][C:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[C:25]([F:33])[CH:26]=3)=[CH:13][N:14]=2)([OH:9])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1F
Reactant: CCN1CCC(O)(c2ncc(I)s2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: COCCOC
Product: CCN1CCC(O)(c2ncc(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)s2)CC1
Temperature: 90 °C

Procedure:
A solution of Example 2A (0.33 g, 0.98 mmol), 4-(tert-butoxycarbonylamino)-3-fluorophenylboronic acid (0.25 g, 0.98 mmol), CsF (0.46 g, 3.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.098 mmol) in a solvent mixture of dimethoxyethane (2 mL) and methanol (1 mL) was heated to 90° C. for 16 h. The reaction was cooled to ambient temperature and diluted with ethyl acetate (5 mL) and H2O (5 mL). The layers were separated, and the organic was washed with 10% aqueous HCl (3×15 mL). 2N NaOH was added to the combined acidic aqueous layers until pH=8. The aqueous layer was extracted with ethyl acetate (3×15 mL). The extracts were then dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title product as a solid. MS (ESI) m/z 422 [M+H]+.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH:16]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:15][N:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(C(CN2CCN(Cc3ccccc3)CC2)c2ccc(F)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1ccc(C(CN2CCNCC2)c2ccc(F)cc2)cc1

Procedure:
35.1 g of 1-benzyl-4-[2,2-bis(4-fluorophenyl)ethyl]-piperazine hydrochloride were hydrogenated in 1,400 ml of methanol on 8 g of palladium-on-charcoal (10%) at room temperature for 1 hour. The catalyst was filtered off with suction, the solvent was evaporated off, the residue was dissolved in 200 ml of water, the pH was brought to 10 with 2N NaOH, the solution was extracted several times with methylene chloride and the extracts were dried and concentrated.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C@@H:9]2[CH2:13][S:12][C:11]([C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=4[NH:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:10]2)[CH2:3]1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41]>ClCCl>[Cl:23][C:19]1[CH:20]=[C:21]2[C:16](=[C:17]([NH:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:18]=1)[NH:15][C:14]([C:11]1[S:12][CH2:13][C@@H:9]([CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:40](=[O:42])[CH3:41])[CH2:3]3)[N:10]=1)=[CH:22]2
Reactant: N[C@H]1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
(2-{(R)-4-[2-((S)-3-amino-pyrrolidin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-chloro-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine (85 mg, 0.19 mmol) prepared in Example 170 was dissolved in dichloromethane (10 mL). Diisopropylethylamine (0.13 mL, 0.75 mmol) and acetylchloride (0.013 mL, 0.19 mmol) were added thereto, and the mixture was stirred for 30 min at room temperature. The reaction was quenched by water, and the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (39 mg, Yield 42%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=O.O>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:18]([O:17][C:11](=[O:16])/[CH:12]=[C:13](\[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][CH3:10])[CH:4]=1)/[CH3:15])[CH3:19]
Reactant: COc1cc(N)ccc1Br
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CCOC(=O)/C=C(/C)Nc1ccc(Br)c(OC)c1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
7.66 g (37.9 mmol) of 4-bromo-3-methoxy-phenylamine (preparation described in Tetrahedron Lett., 1995, 7583) were dissolved in 80 ml of cyclohexane at 70° C. and subsequently treated under stirring with 72 mg (0.38 mmol) of p-toluenesulfonic acid monohydrate and 4.93 g (37.9 mmol) of ethyl acetoacetate. The solution was then heated at reflux for 3.5 h with a water separator funnel connected. It was then cooled to RT and concentrated in vacuo. The residue was applied to a silica gel column with hexane/diethyl ether (3:1) as eluent. Combinations of the purified fractions and concentration in vacuo gave 8.2 g (68.8%) of the (Z)-3-(4-bromo-3-methoxy-phenylamino)-but-2-enoic acid ethyl ester, as a yellow solid. ISP mass spectrum, m/e: 316.2(M+1 calculated for C13H16BrNO3: 316).