Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:16])([CH3:15])[O:9][SiH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[CH3:26][N:27](C)C=O>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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:20]([SiH2:19][O:18][C:17]([CH3:25])([CH3:24])[C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([CH3:16])([CH3:15])[O:9][SiH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1)[C:26]#[N:27])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(Br)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(C#N)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 80 °C
Yield: 82 %

Procedure:
To a solution of 1-bromo-3,5-bis-(tert-butyl-dimethyl-silanyloxymethyl)-benzene (2.05 g, 4.601 mmol, example 35) in dimethylformamide (8 mL) at room temperature was added zinc cyanide (324 mg, 2.761 mmol). The reaction mixture was degassed by passing argon through for 1 h before tetrakis(triphenylphosphine)palladium (319 mg, 0.276 mmol) was added. The reaction mixture was heated at 80° C. under argon for 12 h. The reaction mixture was taken up in toluene (40 mL) and washed with 2 N ammonium hydroxide (2×40 mL), brine and dried over anhydrous magnesium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 5% ethyl acetate in hexanes yielded 3,5-bis-(tert-butyl-dimethyl-silanyloxymethyl)-benzonitrile (1.47 g, 82%).
Reaction SMILES: CO.[CH2:3]([O:6][CH2:7][C@H:8]([NH:13]C(=O)C(F)(F)F)[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]=[CH2:5].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:3]([O:6][CH2:7][C@H:8]([NH2:13])[CH2:9][CH:10]([CH3:11])[CH3:12])[CH:4]=[CH2:5]
Reactant: C=CCOC[C@@H](CC(C)C)NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=CCOC[C@H](N)CC(C)C
Yield: 95 %

Procedure:
Step AK (3): To a mixture of methanol (90 mL) and water (10 mL), (R)-N-(1-(allyloxy)-4-methylpentan-2-yl)-2,2,2-trifluoroacetamide (1.9 g, 7.5 mmol) and potassium carbonate (3.1 g, 22.5 mmol) were added. The mixture was heated at reflux for 16 h and concentrated in vacuum to remove methanol. The mixture was poured into excess NaOH (1 M) and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to yield (R)-1-(allyloxy)-4-methylpentan-2-amine (1.12 g, 95%) as a colorless oil. LC-MS (M+H)+=158.07.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14](Br)=[CH:13][N:12]=2)[CH2:7]1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(N(CC)CC)C>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:13][N:12]=2)[CH2:7]1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ccc(CN[C@H]2CCN(c3ncc(Br)cn3)C2)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)C#Cc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
In a sealed vessel, heat a mixture of (S)-(2,4-dichlorobenzyl)-[1-(5-bromopyrimidin-2-yl)-pyrrolidin-3-yl]-amine (404 mg, 1.01 mmol), (trimethylsilyl)acetylene (250 μL, 1.76 mmol), dichlorobis(triphenylphosphine)palladium (II) (71.4 mg, 0.10 mmol), copper(I) iodide (20.7 mg, 0.11 mmol) and triethylamine (3 mL) at 100° C. for 4 hours. Cool to room temperature and dilute with water (30 mL). Filter through a pad of Celite®, washing with ethyl acetate. Extract the aqueous with additional ethyl acetate (3×50 mL) and wash the combined organics with saturated aqueous sodium chloride (50 mL). Concentrate and dissolve the residue in dichloromethane, filter, and concentrate to give a residue. Chromatograph the residue on silica gel to give (S)-(2,4-dichlorobenzyl)-[1-(5-trimethylsilanylethynylpyrimidin-2-yl)-pyrrolidin-3-yl]-amine as a yellow oil (337 mg, 80%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([Cl:3])=[O:22])=[CH:19][CH:18]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccc(C(=O)Cl)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (12 ml) and dimethylformamide (1 drop) were added to a solution of 4-benzyloxycarbonylaminomethylbenzoic acid (2.85 g) in dichloromethane (12 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was evaporated under reduced pressure to give 4-benzyloxycarbonylaminomethylbenzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (5 ml), and the solution was dropwise added to a mixed solution of 4-amino-1H-pyrazolo[3,4-b]pyridine 2 trifluoroacetate (1.09 g) and diisopropylethylamine (1.7 g) in acetonitrile (10 ml-dimethylformamide (5 ml). The mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and acetonitrile was evaporated under reduced pressure. The residue was extracted with ethyl acetate, dried and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (10 ml) and sodium methoxide (80 mg) was added, which was followed by stirring at room temperature for 4 hours. After the completion of the reaction, insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the obtained residue and the mixture was extracted with chloroform:methanol=10:1. The extract was dried and the solvent was evaporated under reduced pressure. The obtained crystals were washed with ethyl acetate to give 540 mg of N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-benzyloxycarbonylaminomethylbenzamide
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[CH2:5][CH2:4]1.[C:15](=O)([O:18]C)[O:16][CH3:17]>>[O:7]=[C:6]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:14][CH2:3][CH2:4][CH:5]1[C:15]([O:16][CH3:17])=[O:18]
Reactant: O=C1CCCCc2ccccc21
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCCc2ccccc2C1=O
Temperature: 85 °C

Procedure:
A solution of dimethyl carbonate (20 mL) was treated with NaH (3 g, 60% dispersed in oil, 75 mmol) and heated to 85° C. To the mixture was dropwise added a solution of bezosuberone (3 g, 18.75 mmol) in dimethyl carbonate (10 mL). The resulting mixture was refluxed for 3 hours, cooled to 0° C., quenched with HCl (1N) (100 mL) and extracted with ether. The organic layer was washed with NaHCO3 and brine, dried (MgSO4) and concentrated to provide the title compound as a brownish oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)#[N:2].Cl.[NH2:34][OH:35].CC(C)([O-])C.[Na+]>C(O)C>[NH2:2]/[C:1](=[N:34]\[OH:35])/[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(C#N)cc23)cc1
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(/C(N)=N/O)cc23)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 77.2 %

Procedure:
To a mixture of tert-butyl [6-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (3.0 g, 7.0 mmol), hydroxylamine hydrochloride (0.73 g, 11 mmol) and ethanol (75 ml) was added sodium tert-butoxide (1.2 g, 11 mmol), and the mixture was stirred at 70° C. for 6 hrs. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate-tetrahydrofuran and water and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give tert-butyl [6-[(Z)-amino(hydroxyimino)methyl]-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (2.5 g, yield 79%) as a white powder.
Reaction SMILES: [C:1](=O)([O:27]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C@@H:4]([N:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]2[C:17]([CH3:25])=[N:18][C:19]([O:23][CH3:24])=[C:20]([CH3:22])[CH:21]=2)[C:9]1=[O:26])[CH:5]1[CH2:7][CH2:6]1.[CH2:38]([O:40][C:41]1[N:46]=[C:45]([CH3:47])[C:44]([NH2:48])=[CH:43][C:42]=1[CH3:49])[CH3:39].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl>C1COCC1>[CH2:38]([O:40][C:41]1[N:46]=[C:45]([CH3:47])[C:44]([NH:48][C:1](=[O:27])[O:2][CH2:3][C@@H:4]([N:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]3[C:17]([CH3:25])=[N:18][C:19]([O:23][CH3:24])=[C:20]([CH3:22])[CH:21]=3)[C:9]2=[O:26])[CH:5]2[CH2:7][CH2:6]2)=[CH:43][C:42]=1[CH3:49])[CH3:39]
Reactant: CCOc1nc(C)c(N)cc1C
Reactant: COc1nc(C)c(Nc2nc(Cl)cn([C@H](COC(=O)Oc3ccc([N+](=O)[O-])cc3)C3CC3)c2=O)cc1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1nc(C)c(NC(=O)OC[C@H](C2CC2)n2cc(Cl)nc(Nc3cc(C)c(OC)nc3C)c2=O)cc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.5 %

Procedure:
To a solution of (S)-2-(5-chloro-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)-2-oxopyrazin-1(2H)-yl)-2-cyclopropylethyl 4-nitrophenyl carbonate (30 mg, 0.057 mmol) from Part A, 6-ethoxy-2,5-dimethylpyridin-3-amine (17 mg, 0.100 mmol), HOBt (9 mg, 0.063 mmol) and 4 Å molecular sieves (60 mg) in THF (1 mL) at room temperature was added triethylamine (23 μL, 0.17 mmol). The reaction mixture was stirred at room temperature for 48 h. The mixture was transferred to a separatory funnel containing 1 N HCl (5 mL) and the aqueous layer was extracted with EtOAc (3×10 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by HPLC (MeCN/H2O with 0.1% TFA, C18 column) to afford (S)-2-(5-chloro-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)-2-oxopyrazin-1(2H)-yl)-2-cyclopropylethyl 6-ethoxy-2,5-dimethylpyridin-3-ylcarbamate (10 mg, 32% yield) as a yellow amorphous solid: 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.92 (s, 1H), 7.44 (s, 1H), 6.80 (s, 1H), 6.13 (s, 1H), 4.61-4.58 (m, 1H), 4.43 (dd, JAB=11.6, JAX=7.5 Hz, 1H), 4.31 (q, J=6.8 Hz, 2H), 4.26-4.21 (m, 1H), 3.92 (s, 3H), 2.41 (s, 3H), 2.29 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.33 (t, J=7.0 Hz, 3H), 1.25-1.19 (m, 1H), 0.88-0.81 (m, 1H), 0.65-0.55 (m, 2H), 0.38-0.34 (m, 1H); HRMS (ESI) m/e 557.2269 [(M+H)+, calcd for C27H34N6O5Cl 557.2279].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](Br)[C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:27])[N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2B(O)O)[CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:27])[N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[CH:17][CH:16]=2)[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:38]=2[N:29]=[CH:30][CH:31]=[CH:32]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCO)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: OB(O)c1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CN(CCO)C(=O)c1ccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2cccc3cccnc23)cc1
Yield: 108.6 %

Procedure:
Compound 1A (4.0 g, 8.8 mmol), 8-quinolineboronic acid (3.0 g, 17 6 mmol), POPd (0.088 g, 0.18 mmol), and K2CO3 (3.6 g, 26 4 mmol) in iPrOH (90 mL) were stirred in a preheated 100° C. oil bath under nitrogen for 20 h. The reaction was filtered through celite and concentrated. The material was purified by chromatography on silica gel (gradient 2-5% MeOH in CH2Cl2) to give a yellow solid 1B (3.27 g, 74%). 1H NMR (500.333 MHz, CDCl3) δ 8.91 (dd, J=4.0, 1.6 Hz, 1H), 8.13 (dd, J=8.2, 1.5 Hz, 1H), 7.74 (dt, J=9.5, 3.5 Hz, 1H), 7.50 (d, J=2.5 Hz, 2H), 7.37-7.33 (m, 5H), 3.86 (br s, 2H), 3.68 (br s, 2H), 3.59 (br s, 2H), 3.52-3.43 (m, 3H), 3.34-3.23 (m, 2H), 3.03 (s, 3H), 2.57-2.52 (m, 2H), 2.01 (dd, J=19.3, 7.6 Hz, 2H), 1.44 (s, 9H). MS ES+ 502.2.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[F:16][C:17]1[N:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[CH2:24]O)=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Si:7]([O:6][CH2:27][C:23]([C:20]1[CH:19]=[CH:18][C:17]([F:16])=[N:22][CH:21]=1)([CH3:24])[CH3:26])([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9]
Reactant: CC(C)(CO)c1ccc(F)nc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
Tert-butyldimethylsilyl trifluoromethanesulfonate (2.180 mL, 9.49 mmol) was added to a solution of 2-(6-fluoropyridin-3-yl)-2-methylpropan-1-ol (1.46 g, 8.63 mmol) and N,N-diisopropylethylamine (3.31 mL, 18.98 mmol) in CH2Cl2 (43.1 mL) at 0° C., and the resulting mixture stirred at 0° C. for 30 min. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0 to 15% EtOAc/hexanes) to provide 5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluoropyridine (2.22 g, 7.83 mmol, 91% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=2.0 Hz, 1H), 7.79 (td, J=8.2, 2.7 Hz, 1H), 6.85 (dd, J=8.6, 2.9 Hz, 1H), 3.51 (s, 2H), 1.31 (s, 6H), 0.83 (s, 9H), −0.06 (s, 6H). 19F NMR (377 MHz, CDCl3) δ −73.08 (d, J=6.0Hz, 1F). m/z (ESI, +ve) 284.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.P([O-])([O-])([O-])=O.[OH:18][NH3+:19].O[NH3+].O[NH3+]>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:8])[N:19]([OH:18])[C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: [NH3+]O
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: Cc1ccc2c(c1)C(=O)N(O)C2=O

Procedure:
500 mg (3.08 mmol) of 4-methylphthalic anhydride and 243 mg (1.23 mmol) of hydroxylammonium phosphate were mixed and heated with 1 ml of water at a bath temperature of 130° C. for 3 hours. The cooled mixture was digested with 30 ml of water. The precipitate which formed was filtered off with suction and dried at 60° C. under reduced pressure. The yield was 437 mg (80%).
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH:14]([OH:26])[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH2:25][N:16]1[CH2:15][CH:14]([OH:26])[CH2:13][NH:12][C:9](=[O:11])[CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)COc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(COc1ccccc1)NCC(O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.9 %

Procedure:
To a stirred mixture of 2-phenoxyacetic acid (100 mg, 0.658 mmol) in DCM (10 mL) was added TEA (200 mg, 1.98 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (135 mg, 0.658 mmol) and HATU (250 mg, 0.658 mmol). The mixture was stirred at 25° C. for 16 hours then quenched with water (20 mL) and extracted with DCM (3×20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was then purified by prep-HPLC to afford the title compound (76 mg, 34% yield). 1H NMR (400 MHz, CDCl3): δ 7.31-7.27 (m, 2H), 7.14-7.08 (m, 3H), 7.05-6.98 (m, 2H), 6.93 (d, J=8.0 Hz, 2H), 4.54 (s, 2H), 4.55-4.52 (m, 1H), 4.42 (s, 2H), 4.06-4.00 (m, 1H), 3.71 (s, 2H), 3.48-3.38 (m, 2H), 2.91 (d, J=5.6 Hz, 2H), 2.84 (d, J=5.6 Hz, 2H), 2.60 (d, J=6.8 Hz, 2H) ppm. LCMS (m/z): 341.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl-].[NH4+].[CH:13]1C=CC=CC=1.C(OCC)C>>[CH3:13][CH:4]([OH:5])[C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1cccc(Cl)c1Cl
Yield: 90 %

Procedure:
Iodomethane (324.89 g, 2.288 mol) was added dropwise, with stirring, to magnesium turnings (54.88 g, 2.288 mol) in dry ether (1 liter), to form methyl magnesium iodide. 2,3-Dichlorobenzaldehyde (200 g, 1.144 mol) dissolved in benzene/diethyl ether (1 liter, 50:50) solution was added dropwise, with stirring, to the Grignard. The reaction mixture was allowed to stir at room temperature overnight. The solution was refluxed for 2 hours, and then allowed to cool. The reaction mixture was poured into saturated ammonium chloride solution (5 liters) and the organic layer separated. The aqueous layer was extracted with ether (3×2 liters). The organic phases were combined, washed with brine (1×2 liters), dried over anhydrous magnesium sulphate, filtered and evaporated down. α-Methyl-2,3-dichlorobenzyl alcohol (196.4 g, 90% yield) was obtained as a yellow oil which crystallised on standing to give a pale-yellow solid. T.l.c. (SiO2 ;CHCl3) showed no impurities so no further purification was carried out. However, if necessary the alcohol nay be recrystallised from 40-60° C. petroleum ether to afford white prisms of melting point 53° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26]([OH:28])=O)([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])[CH3:2].Cl.[CH3:32][NH:33][CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](=[O:28])[N:33]([CH3:34])[CH3:32])([CH3:24])[CH3:25])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)O)c1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N(C)C)c1)N2
Yield: 91.4 %

Procedure:
2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (820 mg, 2 mmol), dimethylamine hydrochloride (490 mg, 6 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1140 mg, 3 mmol) in dichloromethane (5 mL) and triethyl-amine (1.7 mL, 12 mmol) was stirred at 25° C. for 12 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(1-dimethylcarbamoyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.8 g, 91%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C26H35N3O3 (M+H)+: 438.59, observed: 438.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[CH:5]=[CH:6][CH:7]=1.[Cl:16][CH2:17][C:18](O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:15]=[C:18]2[CH2:17][Cl:16])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccccc1Nc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cccc(-n2c(CCl)nc3ccccc32)c1
Temperature: 130 °C

Procedure:
A mixture of N-(3-fluorophenyl)-o-phenylenediamine (0.8 g, 4 mmol) prepared in the preceding step (a), polyphosphoric ester (2.7 g) and monochloroacetic acid (0.4 g, 4.2 mmol) was heated for 1 hour at 130° C. and water was added to the reaction mixture to decompose an excess of polyphosphoric ester, then neutralized with sodium carbonate and the occurred oily substance was extracted with chloroform and the extract was washed, dried and concentrated in vacuo.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][N:16]1[C:24]2[N:23]=[C:22]([Br:25])[N:21]([CH2:26][C:27]#[C:28][CH3:29])[C:20]=2[C:19](=[O:30])[NH:18][C:17]1=[O:31].[CH:32]1[C:33]([CH2:41]O)=[CH:34][N:35]2[C:40]=1[CH:39]=[CH:38][CH:37]=[CH:36]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(Cl)Cl>[CH:32]1[C:33]([CH2:41][N:18]2[C:19](=[O:30])[C:20]3[N:21]([CH2:26][C:27]#[C:28][CH3:29])[C:22]([Br:25])=[N:23][C:24]=3[N:16]([CH3:15])[C:17]2=[O:31])=[CH:34][N:35]2[C:40]=1[CH:39]=[CH:38][CH:37]=[CH:36]2
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: OCc1cc2ccccn2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1cc3ccccn3c1)c(=O)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.61 ml of diisopropyl azodicarboxylate are added to a mixture of 594 mg of 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine, 353 mg of (indolizin-2-yl)-methanol and 826 mg of triphenylphosphine in 30 ml of tetrahydrofuran. The reaction mixture is stirred for two hours at ambient temperature. For working up it is diluted with methylene chloride, added to 6 g silica gel and chromatographed through a silica gel column with petroleum ether/ethyl acetate (7:3 to 1:5) as eluant.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[C:17]1([CH2:23][CH2:24][CH2:25]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Reactant: BrCCCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(SCCCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, 3-phenylpropyl bromide and sodium ethylate in ethanol. ES-MS m/e (%): 347 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]([Cl:20])([F:19])[S:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:8]=1N.O1CCCC1.N(OC(C)(C)C)=O>O>[Cl:20][C:2]([Cl:1])([F:19])[S:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:8]=1
Reactant: COc1ccc(Cn2ncc(SC(F)(Cl)Cl)c2N)cc1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2cc(SC(F)(Cl)Cl)cn2)cc1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
1.04 g of 4-{[dichlorofluoromethyl]thio}-1-(4-methoxybenzyl)-1H-pyrazole-5-amine was dissolved to 20 ml of tetrahydrofuran. 1.55 g of t-butyl nitrite was added to the solution, followed by refluxed for 3 hours. After the reaction mixture was cooled to room temperature, water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.94 g of 4-{[dichlorofluoromethyl]thio}-1-(4-methoxybenzyl)-1H-pyrazole.