Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O.CCN(S(F)(F)[F:19])CC>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][F:19]
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCCCCCCCCCBr
Solvent: ClCCl
Product: FCCCCCCCCCCBr

Procedure:
Repetition of the procedure described in Example 2 but using 1.00 g (4.23 mmol) of 10-bromodecanol and 0.5287 ml (4.23 mmol) of DAST in 50 mL methylene chloride affords the crude of 10-bromo-1-fluoro-decane. Purification by flash chromatography gives the 10-bromo-1-fluoro-decane (826 mg 3 82%) as a clear colorless liquid: Rf=0.73 hexane/ethyl acetate (7:3, v/v); IR (film) δ2850-3000 (alkane CH); and 1H-NMR (CDCl3) δ1.25-2.95 (m, 16H), 3.36 (t, J=6 Hz, 2H), 4.40 (dt, J=48 Hz, 2H).
Reaction SMILES: N.C([O:5][C@H:6]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][C:18]([C:39]#[N:40])=[N:19][C:20]=3[NH:24][CH2:25][CH:26]2[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:8][C@@H:7]1[CH2:41][O:42]C(=O)C)(=O)C>C(O)C.[Pd]>[NH2:40][CH2:39][C:18]1[N:17]=[C:16]2[C:21]([N:22]=[CH:23][N:15]2[C@H:9]2[C@H:10]([OH:11])[C@H:6]([OH:5])[C@@H:7]([CH2:41][OH:42])[O:8]2)=[C:20]([NH:24][CH2:25][CH:26]2[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:19]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC4c5ccccc5-c5ccccc54)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Agent: N
Solvent: CCO
Product: NCc1nc(NCC2c3ccccc3-c3ccccc32)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 40 h
Yield: 37.7 %

Procedure:
Ammonia gas was passed through an ice cold solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-{2-cyano-6-[(9H-fluoren-9-ylmethyl)amino]-9H-purin-9-yl}tetrahydro-3-furanyl acetate (1.2 g, 2 mmol) (Preparation 71) in ethanol (40 ml) until the solution was saturated. 10% Palladium on carbon (120 mg) was added and the reaction mixture was stirred under an atmosphere of hydrogen gas (413.7 kPa, 60 psi) at room temperature for 40 hours. The suspension was filtered through Arbocel (Trade Mark) and the solvent was removed from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (96:0.4 by volume) increasing in polarity to dichloromethane:methanol:0.88 concentrated aqueous ammonia (94:6:0.5 by volume). The solvent was removed under reduced pressure to give the title compound (358 mg) as a foam.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][O:4]1.[H-].[Na+].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[C:9]1([CH2:8][O:1][CH2:2][CH:3]2[CH2:5][O:4]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCC1CO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCC2CO2)cc1
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To a stirring solution of (+/−)-2-(hydroxymethyl)oxirane (3.0 g, 40.5 mmol, Aldrich) in dry DMF (40 mL) was added sodium hydride (883 mg, 36.8 mmol, Aldrich). The reaction was stirred for 7 min when benzyl bromide (6.3 g, 36.8 mmol, Aldrich) was added. The reaction was stirred for 2 h and then quenched by the addition of water (50 mL). The reaction was extracted with EtOAc (4×50 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and conc. in vacuo to a yellow oil. The oil was purified by flash chromatography (SiO2, 5–20% EtOAc in hexanes) to yield 4.15 g of a colorless oil. MS (ESI) 164 (M+H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25].C(N(CC)CC)C>>[O:25]=[C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23](=[O:24])[N:15]1[CH2:14][CH2:13][CH:12]=[O:11]
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCN1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
The reaction was carried out with oven dried glassware. DMSO (85 μl, 1.1 mmol) was added to oxalyl chloride solution (0.35 mL 2 M DCM solution with 5 mL dry DCM) at −78° C. The reaction mixture was stirred at −78° C. for 10 min. 2-(3-Hydroxy-propyl)-isoindole-1,3-dione solution (102 mg, 0.5 mmol, in 2 mL DCM) was added drop wise in 2 min. Then triethylamine (0.35 mL, 2.5 mmol) was added drop wise in 2 min. The mixture was stirred for additional 30 minutes at −78° C. and was warmed up to room temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over MgSO4, filtered, and the filtrated was concentrated in vacuo. The crude product was purified by flash chromatography to give 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[NH2:21]>O1CCCC1>[I:20][C:18]1[CH:17]=[CH:16][C:15]2[NH:21][C:1](=[O:2])[NH:13][C:14]=2[CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(I)cc1N
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(I)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,1′-Carbonyldiimidazole (13.6 g) was added to a solution of 2-amino-4-iodophenylamine (13.29) [see Makromol. Chem. (1993), 194(3), 859-868] in tetrahydrofuran (100 ml). The reaction mixture was stirred for 18 hours at room temperature, after which time the solvent was removed under reduced pressure, and the residue partitioned between 1N aqueous sodium hydroxide and diethyl ether. The aqueous was acidified with concentrated aqueous hydrochloric acid, and the resulting white precipitate filtered off and washed with water to afford 5-iodo-1,3-dihydro-2H-1,3-benzimidazol-2-one (14.0 g) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]([C:28]1[CH:49]=[CH:48][C:31]([C:32]([NH:34][C@H:35]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:33])=[CH:30][CH:29]=1)=[CH:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:20]=[C:14]2[N:13]=[CH:12]1>C(O)(=O)C.CO.[Pt](=O)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]([C:28]1[CH:49]=[CH:48][C:31]([C:32]([NH:34][C@H:35]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:33])=[CH:30][CH:29]=1)[CH2:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25])[N:20]=[C:14]2[N:13]=[CH:12]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(=Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)COC2CCCCO2)cc1)C(=O)OCC
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(COC2CCCCO2)Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)cc1)C(=O)OCC

Procedure:
A solution of 1.16 g of diethyl N-[4-(1-(tetrahydropyr-2-yloxy)-3-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidin-3-yl)prop-2-en-2-yl)benzoyl]glutamate and 174 mg (20%) of amorphous platinum (IV) oxide in 150 ml of glacial acetic acid is hydrogenated for 10 hours at 50 psi. The reaction mixture is diluted with 50 ml of methanol and filtered through Celite. The filtrate is concentrated and diluted with ethyl acetate. The solid which forms after cooling for 15 hour is collected by filtration, washed with cold ethyl acetate and dried to give diethyl N-[4-(1-(tetrahydropyr-2-yloxy)-3-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidin-3-yl)prop-2-yl)benzoyl]glutamate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([OH:23])=O)=O)=[CH:2]1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]2[N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21](=[O:23])[C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=2)=[CH:2]1
Reactant: Nc1ccccc1
Reactant: O=C(CCc1c[nH]c2ccccc12)Nc1ccccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=c1c2ccccc2nc(CCc2c[nH]c3ccccc23)n1-c1ccccc1
Yield: 31.2 %

Procedure:
To a solution of 3-(3-indolyl)-N-(2-carboxyphenyl)propionamide (6.20 g, 20 mmol) in 50 ml of THF at room temperature was added 1,1-carbonyldiimidazole (3.26 g, 20 mmol). The reaction mixture was stirred under a dry atmosphere for 30 minutes after which aniline (2 ml, 22 mmol) and PPTS (4.03 g, 16 mmol) were added. The resulting reaction mixture was stirred under reflux for two days. The reaction mixture was allowed to cool and evaporated to dryness in vacuo. The product residue was taken up in ethyl acetate and washed (1N HCl, water, saturated NaHCO3, and brine), dried over anhydrous sodium sulfate, and concentrated in vacuo to a brown oil which crystallized from ethyl acetate/hexanes. The product was recrystallized from methanol/ethyl acetate to provide 2.28 g of 2-[2-(3-indolyl)ethyl]-3-phenyl-4-(3H)quinazolinone as white fluffy needles; m.p. 193°-194° C.; FABMS and EIMS 366 (M+); IR (KBr) 1672 CM--1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C@H:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[C:6]([O:8]C(C)(C)C)=[O:7])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C@H:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)O

Procedure:
102 mg (0.20 mMol) of tert.butyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate (melting point: 122-123° C.; [α]D20 =+8.7°; c=1 in methanol) are refluxed in 5 ml of benzene together with a few crystals of p-toluenesulphonic acid hydrate, for half a day. The desired product is then obtained, according to thin layer chromatography, according to the Rf value and mass spectrum.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[C:8]([CH3:21])=[N:9][N:10]2[C:15](O)=[C:14]([CH2:17][CH2:18]O)[C:13]([CH3:20])=[N:12][C:11]=12.C[N:23](C)[C:24]1[CH:29]=[CH:28]C=[CH:26][CH:25]=1>C(OCC)(=O)C>[Br:6][C:7]1[C:8]([CH3:21])=[N:9][N:10]2[C:15]3[N:23]([CH:24]([CH2:29][CH3:28])[CH2:25][CH3:26])[CH2:18][CH2:17][C:14]=3[C:13]([CH3:20])=[N:12][C:11]=12
Reactant: Cc1nc2c(Br)c(C)nn2c(O)c1CCO
Reactant: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCC(CC)N1CCc2c(C)nc3c(Br)c(C)nn3c21
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
Phosphorus oxychloride (3.3 mL) was added to a solution of 3-bromo-6-(2-hydroxyethyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-ol (1.0 mg, 3.50 mmol) in N,N-dimethyaniline (5 mL), followed by stirring at 120° C. for 20 minutes. After cooling to room temperature, the mixture was added dropwise slowly into ice-water under vigorously stirring. Then, the mixture was stirred for two hours while raising a temperature gradually to room temperature, followed by diluting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. 3-Aminopentane (10 mL) was added to a solution of the residue in acetonitrile (30 mL), followed by heating under reflux for three hours. The mixture was diluted with ethylacetate, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crystals were collected by filtration, to give the title compound (700 mg) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13]N1C(=O)CCC1=O>C(#N)C>[Cl:13][C:12]1[CH:11]=[C:5]([CH:4]=[CH:3][C:2]=1[NH2:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCOC(=O)c1ccc(N)c(Cl)c1

Procedure:
To a solution of ethyl 4-aminobenzoate (16 g.) in dry acetonitrile (200 ml.) at 60° was added N-chlorosuccinimide (13.35 g.) over 30 minutes. When the exothermic reaction had subsided the mixture was heated to reflux for 4 hours. After cooling the acetonitrile was removed under vacuum and the residue dissolved in dichloromethane. This was washed with 5% sodium hydroxide solution (2×100 ml.), brine and the organic layer dried over anhydrous magnesium sulphate. Evaporation yielded a solid that was purified by column chromatography on silica eluting with 10% ether/hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[NH:13][C:12]([C:19]([O:21]C)=[O:20])=[CH:11]2.[OH-].[Na+]>CC(C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[NH:13][C:12]([C:19]([OH:21])=[O:20])=[CH:11]2
Reactant: COC(=O)c1cc2cc(OCc3cc(OC)c(OC)c(OC)c3)c(OC)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: COc1cc2[nH]c(C(=O)O)cc2cc1OCc1cc(OC)c(OC)c(OC)c1

Procedure:
180 mg of methyl 5-(3,4,5-trimethoxybenzyloxy)-6-methoxy-1H-indole-2-carboxylate are dissolved in 15 ml of acetone and 3 ml of methanol. 15 ml of 1N sodium hydroxide are added and the mixture is left to react for 2 hours at 30° C. The solvents are evaporated off under vacuum and the residual aqueous phase is acidified to pH=2 with concentrated hydrochloric acid. A solid is obtained, which is purified by taking it up in ethyl acetate at room a temperature.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:33][O:34]COCC[Si](C)(C)C)[C:5]([CH2:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:24]=3[N:23]=2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.B(F)(F)F.O(CC)CC>C(Cl)Cl>[OH:34][CH2:33][C:4]1[C:5]([CH2:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:24]=3[N:23]=2)=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc5cc(C#N)ccc5[nH]4)c(COCOCC[Si](C)(C)C)cc(C)c32)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc5cc(C#N)ccc5[nH]4)c(CO)cc(C)c32)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-((7-methyl-1-tosyl-5-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (133 mg, 0.221 mmol) in CH2Cl2 (10 mL) was added BF3-OEt2 (0.084 mL, 0.664 mmol) at 0° C. The whole mixture was stirred at 0° C. for 1.5 h, and then at room temperature for 2.5 h. The reaction was quenched by 5% aq. NaHCO3 and stirred for 0.5 h. The layers were separated and the aqueous layer was extracted with CH2Cl2. The organic layers were combined and washed with H2O and brine, dried over Na2SO4, and filtered. Concentration of the filtrate gave the title compound, without need of further purification. MS (ESI+) m/z 471.1 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39]([S:44]([N:47]1[CH2:52][CH2:51][N:50]3[CH:53]=[CH:54][CH:55]=[C:49]3[CH:48]1[CH2:56][C:57](O)=[O:58])(=[O:46])=[O:45])[CH:38]=[CH:37]2.[N:60]1([CH2:66][C:67]2[CH:68]=[C:69]3[C:74](=[CH:75][CH:76]=2)[C@H:73]([NH2:77])[CH2:72][CH2:71][CH2:70]3)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>C(Cl)Cl>[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39]([S:44]([N:47]1[CH2:52][CH2:51][N:50]3[CH:53]=[CH:54][CH:55]=[C:49]3[CH:48]1[CH2:56][C:57]([NH:77][C@H:73]1[C:74]3[C:69](=[CH:68][C:67]([CH2:66][N:60]4[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]4)=[CH:76][CH:75]=3)[CH2:70][CH2:71][CH2:72]1)=[O:58])(=[O:45])=[O:46])[CH:38]=[CH:37]2
Reactant: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)O)ccc2c1
Reactant: N[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)N[C@@H]3CCCc4cc(CN5CCCCC5)ccc43)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
DIPEA (2.5 eq.), HOAt (1.0 eq.) and EDCl (1.5 eq.) were added to a solution of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-acetic acid S2 (0.195 mmol, 1.0 eq.) in DCM (3 ml) at 0° C. and the mixture was stirred for 15 min at RT. Then (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydro-naphthalen-1-amine A6 (0.234 mmol, 1.2 eq.) in DCM (2 ml) was added at 0° C. and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and extracted with aqueous NaHCO3 solution, aqueous NH4Cl solution, water and saturated NaCl solution. The organic phase was dried (Na2SO4), concentrated to small volume and purified by column chromatography (alox). Yield: 55%; m/z=627.4 [MH]+
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)CO)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH3:6][O:7][C:8]1([C:14]2[CH:21]=[C:20]([CH:19]=[CH:16][CH:15]=2)[CH2:1][Cl:5])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC1(c2cccc(CO)c2)CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC1(c2cccc(CCl)c2)CCOCC1
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
Carbon tetrachloride (30.3 g, 198 mmol) was added dropwise over 20 minutes to a solution of 3-(4-methxytetrahydropyran-4-yl)benzyl alcohol from Step 4 (29.3 g, 132 mmol) and HMPA (32.2 g, 198 mmol) in THF (400 mL) at 0°-5° C. The mixture was stirred for 10 minutes and then concentrated. Excess Et2O was added and the mixture filtered through a celite pad. The filtrate was concentrated and chromatographed on silica gel using 20% EtOAc in hexane as eluent to obtain 24 g (81%) of the title compound as an oil.
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[CH:16]([CH:27]([CH2:29][CH3:30])[CH3:28])[NH:17][C:18](=[O:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:20]1([CH2:19][C:18]([NH:17][CH:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:32])=[O:8])=[O:31])[CH:27]([CH2:29][CH3:30])[CH3:28])=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: CCC(C)C(NC(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCC(C)C(NC(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
N-phenylacetyl-D,L-isoleucyl-L-proline benzyl ester (1.2 g) was dissolved in methanol (15 ml), and 10% palladium-carbon (120 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a colourless sticky matter (939 mg, 97%), which was directly used for the next reaction.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:23][CH2:22][N:21]3[C:14](=[CH:15][C:16]4[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]=43)[C:13]2=[O:26])=[CH:10][C:9]([F:27])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[CH2:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44]3[C:45](=[O:60])[N:46]([CH3:59])[CH:47]=[C:48](B4OC(C)(C)C(C)(C)O4)[CH:49]=3)=[N:41][CH:42]=2)[CH2:33][CH2:32]1)[CH3:30].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[CH2:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44]3[C:45](=[O:60])[N:46]([CH3:59])[CH:47]=[C:48]([C:7]4[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:11]([N:12]5[CH2:23][CH2:22][N:21]6[C:14](=[CH:15][C:16]7[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]=76)[C:13]5=[O:26])[CH:10]=[C:9]([F:27])[CH:8]=4)[CH:49]=3)=[N:41][CH:42]=2)[CH2:33][CH2:32]1)[CH3:30]
Reactant: CCN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
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: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CCN1CCN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)CC1

Procedure:
To a microwave tube equipped with a stirring bar, 189a (381.9 mg, 0.850 mmol), 3-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (201a) (560 mg, 1.275 mmol), Pd(PPh3)4 (49.1 mg, 0.043 mmol), Na2CO3 aqueous solution (1.0 N, 2.81 mL, 2.81 mmol), 1,2-dimethoxy-ethane (4 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 238a.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[N:15][OH:16])[CH:10]([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: CC(O)C(=O)c1ccc(F)c(F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(O)C(=NO)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a well stirred solution of 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one (5.5 g, 29.6 mmol) in MeOH (200 mL) was added hydroxylamine hydrochloride (2.6 g, 38.4 mmol) and sodium acetate (8.1 g, 59.2 mmol) and the turbid solution was stirred overnight at room temperature. The solvent was evaporated and the residue was extracted with CH2Cl2. The organic layer was washed with sat. NaHCO3, separated, dried over NaSO4 and then filtered. The solvent was removed in vacuo to obtain 1-(3,4-Difluorophenyl)-2-hydroxy-propan-1-one-oxime as an orangish yellow oil (5.3 g, 97%). It was used in the next step without purification.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[OH-].[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CC(C)=O.O>[I:1][C:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[N:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cccc2c(I)n[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(Cn2nc(I)c3cccc([N+](=O)[O-])c32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
3-Iodo-7-nitro-1H-indazole (2.50 g, 8.65 mmol) prepared in Step A was dissolved in acetone (50 mL). Potassium hydroxide (0.73 g, 12.97 mmol) and 4-methoxybenzylchloride (1.63 g, 10.38 mmol) were added in drops thereto at 0° C., and the mixture was stirred for 2 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, 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 (3.2 g, Yield 91%).