Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]#[C:25][Si](CC)(CC)CC)[CH:23]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C.[N:59]([CH2:62][CH2:63][N:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1)=[N+:60]=[N-:61]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]4[N:61]=[N:60][N:59]([CH2:62][CH2:63][N:64]5[CH2:65][CH2:66][O:67][CH2:68][CH2:69]5)[CH:25]=4)[CH:23]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: [N-]=[N+]=NCCN1CCOCC1
Reactant: CC[Si](C#Cc1cncc(-c2cc(-c3cc(Cl)ccc3F)nc3ncccc23)c1)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc(Cl)cc1-c1cc(-c2cncc(-c3cn(CCN4CCOCC4)nn3)c2)c2cccnc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 471 mg (0.994 mmol) 2-(5-chloro-2-fluoro-phenyl)-4-(5-triethylsilanylethynyl-pyridin-3-yl)-[1,8]naphthyridine in 6 ml THF was treated with 1.19 ml of a 1 M solution of tetra-n-butylammonium fluoride in THF and stirred for 1 hour at room temperature. Then 276 μl (1.99 mmol) triethylamine, 190 mg (1.21 mmol) 4-(2-azido-ethyl)-morpholine and 9.5 mg (0.05 mmol) cuprous iodide were added. The reaction mixture was stirred for 66 hours at 70° C. The reaction mixture was cooled to room temperature and partitioned between ethylacetate and brine. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 2-(5-chloro-2-fluoro-phenyl)-4-{5-[1-(2-morpholin-4-yl-ethyl)-1H-[1,2,3]triazol-4-yl]pyridin-3-yl}-[1,8]naphthyridine as colourless solid; HPLC-MS: 1.50 min, [M+H] 516.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13])[CH2:8][O:9][S:33]([CH3:32])(=[O:35])=[O:34]
Reactant: CC(c1ccc(CO)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(c1ccc(COS(C)(=O)=O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-chloro-4-hydroxymethyl-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (50 mg, Example 112) in THF (1 mL) was added NEt3 (30 mg, 0.03 mL) under argon at −10° C. Methanesulfonyl chloride (18 mg, 0.01 mL) was added and the mixture was allowed to stir for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed successively with sat. KHCO3 solution and brine. The organic layer was dried over Na2SO4 and evaporated to give the desired compound as light yellow, viscous oil that was used without further purification (53 mg). MS (m/e)=358.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](=[O:19])[NH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[Cs+].[Cs+].IC>C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](=[O:19])[N:16]([CH3:24])[CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2c1-c1cc[nH]c(=O)c1C(c1ccc(Cl)cc1)=NC2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Solvent: ClCCl
Product: Cc1noc2c1-c1ccn(C)c(=O)c1C(c1ccc(Cl)cc1)=NC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepin-7(8H)-one (0.070 g, 0.215 mmol) in acetonitrile (2 mL) were added cesium carbonate (0.210 g, 0.645 mmol) and iodomethane (16.09 μl, 0.258 mmol) at room temperature. The reaction was stirred at room temperature for 2 h before it was diluted with CH2Cl2 and filtered. The filtrate was concentrated to dryness under vacuum, and the residue was purified by flash chromatography (hexane/EtOAc 9:1 to 3:7) to give 6-(4-chlorophenyl)-1,8-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-one as an off-white solid (0.064 g) and 6-(4-chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine as side product. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J=7.10 Hz, 1H), 7.34 (d, J=2.06 Hz, 4H), 6.67 (d, J=7.10 Hz, 1H), 5.20 (d, J=13.05 Hz, 1H), 4.06 (d, J=13.05 Hz, 1H), 3.43 (s, 3H), 2.51 (s, 3H); LC/MS m/z 340 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4](Br)[CH2:5][CH2:6][CH2:7][CH2:8][Cl:9].[O-:12][C:13]#[N:14].[K+].[CH3:16][OH:17]>C(#N)C.[O-]C#N.CN(C)C(=[N+](C)C)N(C)C>[CH3:1][O:2][C:3](=[O:11])[C:4]([N:14]=[C:13]=[O:12])([O:17][CH3:16])[CH2:5][CH2:6][CH2:7][CH2:8][Cl:9]
Reactant: COC(=O)C(Br)CCCCCl
Reactant: N#C[O-]
Reactant: CO
Agent: CN(C)C(N(C)C)=[N+](C)C
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(CCCCCl)(N=C=O)OC
Yield: 61.4 %

Procedure:
12.78 grams of 2-bromo-6-chlorohexanoic acid methyl ester, 6.08 grams of potassium cyanate, 3.50 grams of methanol and 0.25 gram of hexamethyl guanidinium cyanate were heated in 70 ml of acetonitrile for 25 hours at 80° C. under strong stirring. The reaction mixture was worked up as described in Example 1. There were obtained 7.59 grams (60.7%) of 6-chloro-2-methoxy-carbonylaminohexanoic acid methyl ester which was saponified as in Example 14 to 2-amino-6-chlorohexanoic acid hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:34])[C:24](SC4C=CC(Cl)=CC=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].ClC1C(SC2C=CC(Cl)=CC=2)=CC2N=C(N3C=C(C(O)=O)C=N3)NC=2C=1.[CH:61]1[CH:66]=[C:65]([Cl:67])[CH:64]=[C:63](C(OO)=O)[CH:62]=1.[S:72]([O-:76])([O-])(=[O:74])=S.[Na+].[Na+]>C([O-])(O)=O.[Na+].ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:34])[C:24]([S:72]([C:62]4[CH:61]=[CH:66][C:65]([Cl:67])=[CH:64][CH:63]=4)(=[O:76])=[O:74])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Sc4ccc(Cl)cc4)c(Cl)cc3n2COCCOC)c1
Reactant: O=S([O-])([O-])=S
Agent: O=C(O)c1cnn(-c2nc3cc(Sc4ccc(Cl)cc4)c(Cl)cc3[nH]2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)c4ccc(Cl)cc4)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a solution of 1-[6-chloro-5-(4-chloro-phenylsulfanyl)-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 61) (2.69 g, 5.16 mmol) and dichloromethane (26 mL) was added mCPBA (2.43 g, 10.8 mmol) at 23° C. The reaction was stirred for 16 h at 23° C. Dichloromethane (30 mL) was added followed by a solution of sodium thiosulfate (1.71 g, 10.8 mmol) in 80% saturated aqueous NaHCO3 (30 mL). The mixture was stirred vigorously until both layers were clear. The organic layer was collected and the aqueous layer extracted with CH2Cl2 (2×80 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-100% EtOAc/hexanes) to yield the titled compound (2.55 g, 89%) as a mixture of regioisomers. MS (ESI/CI): mass calcd. for C23H22Cl2N4O6S, 552.1; m/z found, 553.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.91-8.89 (m, 2H), 8.73 (s, 1.4H), 8.68 (s, 0.6H), 8.20 (d, J=0.6 Hz, 0.6H), 8.18 (d, J=0.6 Hz, 1.4H), 7.91-7.87 (m, 4H), 7.72 (s, 0.6H), 7.68 (s, 1.4H), 7.48-7.43 (m, 4H), 6.27 (s, 1.2H), 6.15 (s, 2.8H), 4.39-4.32 (m, 4H), 3.71-3.66 (m, 1.2H), 3.67-3.62 (m, 2.8H), 3.48-3.45 (m, 1.2H), 3.44-3.40 (m, 2.8H), 3.28 (s, 1.8H), 3.24 (s, 4.2H), 1.40-1.34 (m, 6H).
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[C:6]([CH:16]([S:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:7][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][CH:10]=1.ClC1C=CC=C(C(OO)=[O:41])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCOCC.CCCCCC>[Cl:4][C:5]1[C:6]([CH:16]([S:25]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[O:41])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:7][C:8]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])=[N:9][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)Nc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCCC
Product: CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 82.2 %

Procedure:
To a methylene chloride (10 ml) solution of N-[5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanesulfonamide (331 mg, 0.696 mmol) was added 3-chloroperbenzoic acid (120 mg, 0.696 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 50 minutes. At the same temperature, 3-chloroperbenzoic acid (60 mg, 0.348 mmol) was added to the reaction mixture. After stirring at 0° C. for 10 minutes, a saturated aqueous solution of sodium thiosulfate was added to the reaction mixture. The resulting mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure. To the residue thus obtained was added ether and the solid thus precipitated was collected by filtration to give the title compound (281 mg, 0.572 mmol, 82%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(N)ccc1Cl
Reaction time: 16 h

Procedure:
A solution of 10 g of 2-chloro-5-(amino)benzoic acid in 250 mL of methanol was saturated with HCl (gas) and stirred for 16 h. The solution was concentrated in vacuo, diluted with water, made neutral with 5N NaOH and extracted twice with ether. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to afford 10 g of title compound as a slightly pink solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][NH2:10].[CH3:15][S:16][C:17]1[C:22]([N:23]=[C:24]=[O:25])=[C:21]([S:26][CH3:27])[CH:20]=[C:19]([CH3:28])[N:18]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:15][S:16][C:17]1[C:22]([NH:23][C:24]([NH:10][CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:25])=[C:21]([S:26][CH3:27])[CH:20]=[C:19]([CH3:28])[N:18]=1
Reactant: CCCCC(CN)c1ccccc1C
Reactant: CSc1cc(C)nc(SC)c1N=C=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(CNC(=O)Nc1c(SC)cc(C)nc1SC)c1ccccc1C
Temperature: 25 °C
Yield: 32.9 %

Procedure:
A solution of 2-(2-methylphenyl)hexylamine (153 mg, 0.8 mmol) and 2,4-bis(methylthio)-6-methylpyridin-3-yl isocyanate (180 mg, 0.8 mmol) in 3 ml dimethylformamide was heated at 80° C. under nitrogen overnight. The reaction mixture was cooled to room temperature and diluted with 60 ml ethyl acetate. The resulting solution was washed sequentially with 3×50 ml water and 50 ml brine, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed on silica gel (200 g), eluting with 7:3 hexane/ethyl acetate to yield the title compound as a white solid (110 mg, 33% yield).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][O:10][C:11](=[O:15])[CH:12]=[CH:13][CH3:14]>>[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH:13]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH3:14]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CC=CC(=O)OC
Product: COC(=O)CC(C)n1cnc([N+](=O)[O-])c1

Procedure:
4-nitroimidazole was reacted with methyl-3-methylacrylate to provide the title compound: 1H NMR (400 MHz, CDCl3) 1.62 (d, 3H, J=7.0 Hz), 2.81 (d, 2H, J=7.0 Hz), 3.66 (s, 3H), 4.78 (m, 1H), 7.53 (d, 1H, J=1.6 Hz), 7.82 (d, 1H, J=1.6 Hz); MS m/z 214.1(M+1).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[CH2:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][NH:12]1>C(OCC)(=O)C>[CH:5]([N:12]1[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:11]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCCNC2
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=CN1CCCc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (20 ml) was added dropwise to formic acid (60 ml) at room temperature and after the mixture was stirred for 30 minutes, a solution of 2,3,4,5-tetrahydro 1H-2-benzazepine (10.71 g, 72.75 mmol) in ethyl acetate (5 ml) was added dropwise at room temperature. This mixture was stirred for 3 hours, after which it was diluted with ice-water and extracted with ethyl acetate. The extract was washed successively with water, aqueous solution of potassium carbonate (K2CO3), and saturated NaCl/H2O and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide the title compound (11.35 g) as colorless oil.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C(Cl)C=1O.C([Zn]CC)C.C(I)I.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[CH2:27])=[CH:22][CH:21]=1>C(Cl)Cl.CCCCC>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2([O:28][CH3:29])[CH2:2][CH2:27]2)=[CH:24][CH:25]=1
Reactant: C=C(OC)c1ccc(Br)cc1
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Agent: CC[Zn]CC
Solvent: ClCCl
Solvent: CCCCC
Solvent: ICI
Product: COC1(c2ccc(Br)cc2)CC1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
To a solution of 2,4,6-trichlorophenol (1.90 g, 9.64 mmol) in methylene chloride (70 ml) at −40° C. was added diethyl zinc (9.64 ml, 1M solution in hexane, 9.64 mmol). The mixture was stirred at −40° C. for 20 min and then CH2I2 (778 μl, 9.64 mmol) was added. After stirring for an additional 20 min, 1-bromo-4-(1-methoxyvinyl)-benzene (1.37 g, 6.43 mmol) was added. The reaction mixture was slowly warmed to RT and stirring was continued for 16 h. Pentane was added and the mixture was washed with 1M HCl, sat. NaHCO3, sat. Na2SO3 and brine. The organic layer was dried (MgSO4), filtered, concentrated in vacuo to give a crude residue which was purified by flash column chromatography (2% ethyl acetate in cyclohexane-10% ethyl acetate in cyclohexane) to give 1-bromo-4-(1-methoxycyclopropyl)-benzene (880 mg, 60%) as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ 7.46 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 3.21 (s, 3H), 1.21-1.17 (m, 2H), 0.95-0.91 (m, 2H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([Br:9])[CH:3]=1.[CH3:10][C:11](=[CH2:19])[C:12]([O:14][CH2:15][CH:16]([OH:18])[CH3:17])=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:19][C:11](=[CH2:10])[C:12]([O:14][CH2:15][CH:16]([O:18][C:7]1[CH:6]=[CH:5][C:4]([Br:9])=[CH:3][CH:2]=1)[CH3:17])=[O:13]
Reactant: Oc1ccc(O)c(Br)c1
Reactant: C=C(C)C(=O)OCC(C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCC(C)Oc1ccc(Br)cc1

Procedure:
Following the same preparation procedure of Example 2, the reaction was carried out with 4-hydroxy bromophenol (4 g), 2-hydroxypropyl 2-methylacrylate (3.33 g), triphenyl phosphine (6.06 g) and DIAD (4.69 g) in 50 ml of THF to give after chromatography purification pure 2-(4-bromophenoxy)propyl 2-methylacrylate as pale yellow oil.
Reaction SMILES: C(O[C:4]1(O[Si](C)(C)C)[CH2:6][CH2:5]1)C.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.C[Si]([C:23]#[N:24])(C)C.CCCCCCC.C(OCC)(=O)C>C(OCC)(=O)C>[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:4]2([C:23]#[N:24])[CH2:5][CH2:6]2)[CH2:14]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: C[Si](C)(C)C#N
Reactant: CC1CCCNC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC1CCCN(C2(C#N)CC2)C1
Yield: 79 %

Procedure:
The reaction of (1-ethoxycyclopropoxy)trimethylsilane 13 and 3-methylpiperidine 14B with trimethylsilylcyanide yielded after column chromatography with a gradient of heptane/ethyl acetate (v:v 4:1) to ethyl acetate as solvent 1-(3-methylpiperidin-1-yl)cyclopropanecarbonitrile as a colorless oil (79%). MS ISP (m/e): 165.2 (100) [(M+H)]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[C:25]([O:27]C)=[O:26].O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[C:19]([O:18][CH3:17])[CH:20]=2)=[CH:3][C:4]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
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: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (300 mg, 1.06 mmol) and (3-methoxy-4-(methoxycarbonyl)phenyl)boronic acid (245 mg, 1.16 mmol) in 1,4-dioxane (10.0 mL)/water (5.0 mL) was added Cs2CO3 (1.0 g, 3.18 mmol) at room temperature. The reaction mixture was degassed with argon for 30 min. Then Pd(PPh3)4 (61 mg, 0.05 mmol) was added and allowed to stir at 120° C. for 30 min in CEM micro wave. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The aqueous layer was neutralized with 1N HCl, extracted with DCM (2×50 mL), washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. The crude compound was washed with diethyl ether to afford 260 mg (yield: 69.33%) of the title compound as pale yellow solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=1)[C:28]([C:41](O)=[O:42])=[CH:27]2.[NH2:44][C:45]1[CH:46]=[N:47][C:48]([N:51]2[CH2:54][CH2:53][CH2:52]2)=[CH:49][CH:50]=1>CN(C=O)C.C(OCC)(=O)C.O>[N:51]1([C:48]2[N:47]=[CH:46][C:45]([NH:44][C:41]([C:28]3[N:29]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=4)[C:30]4[C:26]([CH:27]=3)=[CH:25][C:24]([Br:23])=[CH:32][CH:31]=4)=[O:42])=[CH:50][CH:49]=2)[CH2:54][CH2:53][CH2:52]1
Reactant: Nc1ccc(N2CCC2)nc1
Reactant: O=C(O)c1cc2cc(Br)ccc2n1Cc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc(Br)ccc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 594.7 %

Procedure:
0.77 g (4.02 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and 0.54 g (4.02 mmol) of 1-hydroxybenzotriazole (HOBT) are added to a solution, stirred at 20° C. under an inert atmosphere, of 1.4 g (4.02 mmol) of 5-bromo-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared in stage 17.2, in 20 ml of DMF. The reaction mixture is stirred at ambient temperature for 20 minutes. 0.66 g (4.42 mmol) of 3-amino-6-(azetidin-1-yl)pyridine, prepared according to the protocol described in stage 1.6, is subsequently added to the reaction mixture. After stirring at 20° C. for 18 hours, the reaction mixture is poured into a mixture of 50 ml of water and 50 ml of ethyl acetate. The resulting mixture is separated by settling out and the aqueous phase is extracted with 20 ml of ethyl acetate. The combined organic phases are washed three times with 30 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The isolated product is subsequently precipitated, then washed with isopropyl ether at reflux, filtered under hot conditions, and then dried under reduced pressure. 11.46 g of the expected product are thus isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[H-].[Na+].[O:11]=[C:12]1[C:24]2[C:19](=[N:20][C:21](C#N)=[C:22]([C:25]#[N:26])[N:23]=2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2.CO>CN(C=O)C>[C:6]([C:5]([C:21]1[N:20]=[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:11])[C:24]2=[N:23][C:22]=1[C:25]#[N:26])=[C:4]([O:3][CH2:1][CH3:2])[OH:8])#[N:7]
Reactant: N#Cc1nc2c(nc1C#N)-c1ccccc1C2=O
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(O)=C(C#N)c1nc2c(nc1C#N)C(=O)c1ccccc1-2
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Ethylcyanoacetate (110 mg, 0.970 mmol) was dissolved, under inert atmosphere, in dry DMF (1 ml) and NaH (39 mg, 0.970 mmol) was added in one portion. After 30 min, a solution of 1 (150 mg, 0.646 mmol) in dry DMF (2 ml) was added dropwise. After 15 min MeOH was added and the solution stirred for 10 min. The solvents were evaporated and the crude purified by flash chromatography (EtOAc:MeOH 9:1) affording 22 as a dark red solid (200 mg, 97%).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([Br:14])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([Br:14])[CH:8]=1
Reactant: CO
Reactant: NC(CC(=O)O)c1cc(F)cc(Br)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1cc(F)cc(Br)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
1.59 g (6.05 mmol) 3-amino-3-(3-bromo-5-fluorophenyl)propionic acid were suspended in 24.5 ml methanol and the mixture cooled to 0° C. 0.66 ml (9.08 mmol) thionyl chloride were slowly added. The mixture was stirred at room temperature for 20 hours and concentrated. The residue was treated with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic part was dried with sodium sulfate and concentrated. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 1.55 g (93%) 3-amino-3-(3-bromo-5-fluorophenyl)propionic acid methyl ester.