Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][C:23](=[O:28])[N:24]2[CH3:27])=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1>>[F:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][C:23](=[O:28])[N:24]2[CH3:27])=[CH:19][C:18]=1[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Product: CCC(=O)NC1CCc2c(-c3cc4c(cc3F)N(C)C(=O)CC4)cncc21
Yield: 72 %

Procedure:
In analogy to the procedure described for the preparation of intermediate A-2 [E], (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-3) was reacted with 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-9) to give the title compound as a light brown solid in 72% yield. MS: 368.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][C:8]#[N:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[OH2:16].Cl.[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[C:8]([CH2:7][CH:6]([C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]([C:12]([F:13])([F:14])[F:15])[CH:4]=1)[CH:19]([C:2]1[CH:11]=[CH:10][CH:5]=[CH:4][CH:3]=1)[C:20]([O:21][CH2:22][CH3:18])=[O:16])#[N:9]
Reactant: C1CCOC1
Reactant: O
Reactant: N#CC=Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Product: CCOC(=O)C(c1ccccc1)C(CC#N)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
20 g (0.086 mol) of 4-chloro-3-trifluoromethylcinnamonitrile dissolved in 80 cm3 of anhydrous THF are added in the course of 45 min at a temperature of between -12° C. and -15° C. The temperature is allowed to rise to -5° C. and the mixture is stirred for 1 hour 10 min before being hydrolyzed at between -5° C. and -10° C. with 50 cm3 of water and then 6N hydrochloric acid (approximately 40 cm3) to neutrality.
Reaction SMILES: [C:1]([C:9]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[N:32]=[C:33]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[O:34][C:35]=3[CH3:36])=[CH:25][CH:24]=2)=[CH:17][C:10]=1[O:11][CH2:12][C:13]([O:15]C)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[C:1]([C:9]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[N:32]=[C:33]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[O:34][C:35]=3[CH3:36])=[CH:25][CH:24]=2)=[CH:17][C:10]=1[O:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc1C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(C(=O)c3ccccc3)c(OCC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of methyl 2-[2-benzoyl-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenoxy]acetate (0.55 g), tetrahydrofuran (1.5 mL) and methanol (1.5 mL) was added a 1N aqueous sodium hydroxide solution (1.5 mL) and the mixture was stirred at room temperature for 3 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 2-[2-benzoyl-5-[4[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenoxy]acetic acid as a colorless amorphous compound (0.41 g, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([O:7][C:8]1[C:9](Cl)=[N:10][C:11]([Cl:15])=[N:12][C:13]=1[Cl:14])[CH3:6])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:17])[C@H:5]([O:7][C:8]1[C:13]([Cl:14])=[N:12][C:11]([Cl:15])=[N:10][C:9]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)[C@@H](C)Oc1c(Cl)nc(Cl)nc1Cl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@@H](C)Oc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
A mixture of (R)-2-(2,4,6-trichloro-pyrimidin-5-yloxy)-propionic acid ethyl ester (522 mg, 1.74 mmol), morpholine (152 μL, 1.74 mmol) and triethylamine (484 μL, 3.48 mmol) in ethanol (15 mL) was stirred at RT for 18 hours then partitioned between ethyl acetate and water. The aqueous phase was extracted with further ethyl acetate and the combined organic extracts dried (Na2SO4) and concentrated in vacuo affording (R)-2-(2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-propionic acid ethyl ester (490 mg, 80%). LCMS: RT=3.57 min, [M+H]+=350/352.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[CH:4][C:3]=1[F:31]>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[CH:4][C:3]=1[F:31]
Reactant: CSCc1cccc2c(C(c3ccc(Cl)c(F)c3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(Cl)c(F)c1)c1c[nH]c2c(CSC)cccc12

Procedure:
17 mg (262 μmol) of copper powder were added to a solution of 2.42 g (5.24 mmol) of the compound from Example 95A in 10 ml of pyridine and 2 ml of ethanol. The reaction mixture was heated under reflux for 4 h. It was concentrated, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 1.82 g (85% of theory) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C@:10]2([O:32][C@H:31]([CH2:33][O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:13]2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(O)(=O)C.[PH:53](=[O:60])([O:57][CH2:58][CH3:59])[O:54][CH2:55][CH3:56]>CCOCC>[CH2:55]([O:54][P:53]([O:57][CH2:58][CH3:59])([CH:11]([OH:12])[C@:10]1([CH2:9][O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:32][C@H:31]([CH2:33][O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C@@H:22]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:60])[CH3:56]
Reactant: CCO[PH](=O)OCC
Reactant: O=C[C@]1(COCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C(O)[C@]1(COCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A 7.20 g portion of 2,5-anhydro-2-C-[(phenylmethoxy)methyl]-3,4,6-tris-O-(phenylmethyl)-D-glucose was dissolved in 6.7 ml of phosphonic acid, diethyl ester and treated with 620 μl of triethylamine under argon. After 4.5 hours 800 μl of acetic acid was added, the resulting yellow oil taken up in ether, washed with water, saturated with hexane, rewashed with water, then twice with brine, dried and evaporated. The residual oil was flash chromatographed, eluting 75 ml fractions with ether:toluene (2:1).
Reaction SMILES: [Mg].Br[CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5].[CH3:8][C:9](=[CH:12][CH2:13][CH3:14])[CH:10]=[O:11]>CCOCC>[CH3:8][C:9]([CH:10]([OH:11])[CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5])=[CH:12][CH2:13][CH3:14]
Reactant: CCC=C(C)C=O
Reactant: CCC(Br)CC
Agent: [Mg]
Solvent: CCOCC
Product: CCC=C(C)C(O)C(CC)CC

Procedure:
A Grignard reagent, prepared by reacting 29.4 g (1.21 g atoms) of magnesium in 200 ml of ether and 183 g (1.21 mol) of 3-bromopentane in 400 ml of ether, is reacted with 98.0 g (1.0 mol) of 2-methyl-2-pentenal in a manner analogous to Example 5. Fractional distillation of the crude product (159.3 g) over a 20 cm Widmer column gives 95.5 g (56.2%) of olfactorily good 4-methyl-6-ethyl-3-octen-5-ol of melting point 92°-93° C./12 mm Hg.
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH2:20][O:21]C(=O)C)[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:19])=[N:13][C:14]=2Cl)(=O)C.[OH-:25].[Na+]>Cl>[OH:4][CH2:5][CH:6]([CH2:20][OH:21])[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:25])[NH:13][C:12]([NH2:19])=[N:11][C:10]1=2
Reactant: [OH-]
Reactant: CC(=O)OCC(CCn1cnc2c(Cl)nc(N)nc21)COC(C)=O
Agent: Cl
Agent: [Na+]
Product: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Yield: 85 %

Procedure:
A solution of 9-(4-acetoxy-3-acetoxymethyl-but-1-yl)-2-amino-6-chloropurine (15.5 g, 43.6 mmol) in 2M hydrochloric acid (150 ml) was heated under reflux for 2 hours. The solution was then cooled to room temperature and neutralised with 10% sodium hydroxide solution, left to stand at 4° C., and the resulting precipitate filtered off, washed with cold water and recrystallized from water to give 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine as a white crystalline solid (9.4 g, 85%) mp 275-277°.
Reaction SMILES: CN([CH:4]=[O:5])C.O[C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([OH:17])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O>[CH2:25]([O:17][C:15]1[CH:14]=[C:9]([CH:8]=[C:7]([O:5][CH2:4][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CCCCCCCCCCCCBr
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCCCOc1cc(OCCCCCCCCCCCC)cc(C(=O)OC)c1
Reaction time: 8 h

Procedure:
In a 1 L RBF containing a stir bar and DMF (100 mL); methyl 3,5-dihydroxylbenzoate (20 g, 0.1190 M), potassium carbonate (49.34 g, 0.3570 M), 1-bromododecane (57.2 mL, 0.2380 M) and DMF (100 mL) were added. The reaction mixture was covered with a septum and stirred overnight. By the end of the reaction period (15 hours), the reaction mixture had turned from a pale yellow suspension to a solid dark green suspension. Heat was applied to the RBF until the reaction mixture became fluid. The dark green mixture was then added to 1 L of distilled water and ice, and copious precipitation occurred immediately. The precipitate was isolated by vacuum filtration. The precipitate was recrystallized from hot ethanol (1 L). To increase the product yield, the solution was left to stand at room temperature overnight. The crystals were vacuum filtered and the crystals air-dried yielding 58.5 g or 96.7%. The NMR characterization data for the derivative is as follows. 1H NMR (300 MHz, CDCl3): 0.87 (t, J=6.6, 6H, CH2CH3), 1.15-1.6 (m, 28H, CH2(CH2)6), 1.76 (p, J=8.0, 8H, OCH2CH2), 3.89 (s, 3H, OCH3), 3.95 (t, J=6.6, 4H, OCH2CH2), 6.62 (t, J=2.5, 1H, ArH), 7.15 (d, J=2.5, 2H, ArH).
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:21])OC2C=CC([N+]([O-])=O)=CC=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[NH2:30][C@@H:31]1[C:40]([CH2:43][CH3:44])([CH2:41][CH3:42])[C:39]2[CH:38]=[C:37]([C:45]([NH2:47])=[O:46])[CH:36]=[CH:35][C:34]=2[CH2:33][C@H:32]1[O:48][CH3:49]>CN(C)C=O>[C:1]1([C@H:7]([O:9][C:10](=[O:21])[NH:30][C@@H:31]2[C@@H:32]([O:48][CH3:49])[CH2:33][C:34]3[C:39](=[CH:38][C:37]([C:45](=[O:46])[NH2:47])=[CH:36][CH:35]=3)[C:40]2([CH2:43][CH3:44])[CH2:41][CH3:42])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1N
Reactant: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NC(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of carbonic acid 4-nitro-phenyl ester (R)-1-phenyl-ethyl ester (102 g, 357 mmol), N,N-dimethylformamide (200 mL) and triethylamine (32.7 mL, 235 mmol) was stirred at room temperature overnight. To the reaction mixture was added trans-7-amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide hydrochloride (100 g, 320 mmol), N,N-dimethylformamide (320 mL) and triethylamine (98.0 mL, 703 mmol). The reaction mixture was heated at 85° C. for 5 h and then stirred at room temperature overnight. Approximately 90% of the DMF was removed by distillation at 70° C. and the resulting thick oil was cooled to room temperature and then partitioned between ethyl acetate (1.5 L) and diluted brine (500 mL). The organic layer was washed with 1M NaOH (3×500 mL) and dried with Na2SO4. Most of the solvent was removed by rotary evaporation, 3 volumes ethyl acetate were added and resulting slurry was stirred at room temperature for 30 min, filtered and dried to give the title compound (48 g, >99% chemical and optical purity).
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].C(Cl)(Cl)Cl.C(=O)=O.[Br:12][C@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=[O:15].S(=O)(=O)(O)O>ClCCl>[C:2]([O:16][C:14](=[O:15])[C@H:13]([Br:12])[CH2:17][CH:18]([CH3:20])[CH3:19])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)C[C@@H](Br)C(=O)O
Reactant: C=C(C)C
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@@H](Br)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Into dichloromethane (80 mL) was condensed isobutene to double the volume (at -50° C. CHCl3 /dry ice). To this solution was added (2R)-2-bromo-4-methylpentanoic acid (28 g, 143.6 mmol) and maintaining the temperature between -400 and -50° C. concentrated sulphuric acid (1 mL) was added dropwise. The reaction was then allowed to warm to room temperature over 20 hours. The solution was then concentrated before adding additional methylene chloride (300 mL) which was subsequently washed with saturated NaHCO3 (2×100 mL) followed by water (2×100 mL). After drying over Na2SO4, the organic layer was filtered and concentrated to give a yellow oil. The material was distilled to give 23 g of (2R)-2-bromo-4-methylpentanoic acid t-butyl ester as a clear colorless oil.
Reaction SMILES: [CH2:1]1[CH2:25][O:24][C:3]2([CH2:20][CH2:19][C@@:18]3([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]4[C@:17]3([OH:22])[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=O)[CH2:4]2)[O:2]1.NCCN.[N+:30]([CH3:33])([O-:32])=[O:31]>>[CH2:1]1[CH2:25][O:24][C:3]2([CH2:20][CH2:19][C@@:18]3([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]4[C@:17]3([OH:22])[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[CH:33][N+:30]([O-:32])=[O:31])[CH2:4]2)[O:2]1
Reactant: C[N+](=O)[O-]
Reactant: C[C@]12CCC3(CC1=CC[C@H]1[C@@H]4CCC(=O)[C@@]4(C)CC[C@@]12O)OCCO3
Solvent: NCCN
Product: C[C@]12CCC3(CC1=CC[C@H]1[C@@H]4CCC(=C[N+](=O)[O-])[C@@]4(C)CC[C@@]12O)OCCO3
Temperature: 25 °C

Procedure:
To a solution of 3,3-ethylenedioxy-9α-hydroxyandrost-5-en-17-one (3.46 g) in nitromethane (75 ml) under a nitrogen atmosphere 1,2-diaminoethane (0.1 ml) was added at reflux temperature. After 24 hours of refluxing the reaction was almost complete as measured by TLC. After cooling to room temperature the reaction mixture was concentrated under reduced pressure to give a solid, which was purified by column chromatography (silica gel; methylene chloride/diethyl ether 1/1) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2.[OH-].[K+].I[CH3:21]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:21])[C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2
Reactant: CI
Reactant: CCCCCCCc1cc2cc(Cl)ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCc1cc2cc(Cl)ccc2n1C
Reaction time: 0.5 h

Procedure:
To the solution of 5-chloro-2-heptyl-1H-indole in DMSO was added KOH at RT and was stirred for 30 minutes. Then to this mixture, iodomethane was added and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product, 5-chloro-2-heptyl-1-methyl-1H-indole was purified by column chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.[CH3:47][S:48][C:49]1[C:57]2[C:52](=[CH:53][C:54]([NH2:58])=[CH:55][CH:56]=2)[N:51]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[N:50]=1>ClCCl>[CH3:47][S:48][C:49]1[C:57]2[C:52](=[CH:53][C:54]([NH:58][C:15](=[O:17])[CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:55][CH:56]=2)[N:51]([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:50]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: CSc1nn(-c2ccccc2)c2cc(N)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CSc1nn(-c2ccccc2)c2cc(NC(=O)CC3CCCCN3C(=O)OC(C)(C)C)ccc12
Temperature: 15 °C
Reaction time: 0.17 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(1-(tert-butoxycarbonyl)piperidin-2-yl)acetic acid (0.47 mg), 1H-benzo[d][1,2,3]triazol-1-ol (300 mg, 1.96 mmol), EDC.HCl (370 mg, 1.94 mmol), 4-methylmorpholine (590 mg, 5.84 mmol, 2.98 equiv) in dichloromethane (3 mL). The resulting solution was stirred for 10 min at 15° C. A solution of 3-(methylthio)-1-phenyl-1H-indazol-6-amine (500 mg, 1.96 mmol, 1.00 equiv) in dichloromethane (3 mL) was added. The resulting solution was stirred for an additional 2 h at 15° C. The resulting mixture was washed with aq. sodium bicarbonate (1×8 mL) and brine (2×8 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10˜1:3) to yield tert-butyl 2-(2-(3-(methylthio)-1-phenyl-1H-indazol-6-ylamino)-2-oxoethyl)piperidine-1-carboxylate as a white solid. MS: 481 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[Cl:31]C1C=C(C=CC=1OC)C=O>>[Cl:31][C:30]1[CH:29]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: COc1ccc(C=O)cc1Cl
Product: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1Cl

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 3-chloro-4-methoxybenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 456 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.28 (1H, s) 7.98-8.07 (2H, m) 7.77 (1H, d, J=5.42 Hz) 7.46 (1H, d, J=5.42 Hz) 7.36 (1H, d, J=2.15 Hz) 7.30 (1H, dd, J=3.51, 2.39 Hz) 7.20 (1H, dd, J=8.42, 2.12 Hz) 7.00 (1H, d, J=8.44 Hz) 6.80 (1H, d, J=5.52 Hz) 6.43 (1H, dd, J=3.54, 1.88 Hz) 3.80 (3H, s) 3.61 (2H, s) 2.60 (2H, t, J=6.59 Hz)
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH2:58]O)[C@@H:47]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:15][CH:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:75])CC)C.CO.C(OCC)(=O)C>COCCOC>[CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH2:58][F:75])[C@@H:47]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:15][C@@H:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Solvent: COCCOC
Product: C=CCO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](CF)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
The compound (6.43 g, 6.97 mmol) synthesized in Example 2 (2c) was dissolved in 1,2-dimethoxyethane (130 mL) and diethylaminosulfur trifluoride (2 mL, 20.50 mmol) was added thereto, followed by stirring of the mixture at 60° C. for 1 hour. Methanol (10 mL) was added to the reaction mixture under ice-cooling and the mixture was stirred for 30 minutes. After ethyl acetate (50 mL) was added thereto and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (50 mL) and saturated brine (50 mL) and dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 6:1, V/V) to obtain the desired title compound (5.06 g, yield 78%) as a yellow solid.
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[N:37]1([C:20]2[CH:28]=[CH:27][C:26]([S:29]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCCC2)ccc1Cl
Reactant: C1COCCN1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: O=C(O)c1cc(S(=O)(=O)N2CCCC2)ccc1N1CCOCC1
Yield: 34 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(pyrrolidine-1-sulfonyl)-benzoic acid and morpholine and obtained in 34% yield. MS (m/e): 339.2 (MH−, 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH2:11]([NH2:14])[C:12]#[CH:13].O>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:14][CH2:11][C:12]#[CH:13])[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: C#CCN
Solvent: CC#N
Solvent: O
Product: C#CCNc1cc(Cl)nc(SC)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 99.4 %

Procedure:
A mixture of 1.00 g (5.13 mmol) of 4,6-dichloro-2-(methylthio)pyrimidine and 0.7 ml (10.3 mmol) of propargylamine in 10 ml of acetonitrile was stirred for 12 hours at 60° C. The reaction solution was poured onto cold water. Then, the formed precipitate was filtered, washed several times with cold water and dried. 1.09 g of a light yellow solid were obtained.