Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31]>CC(C)=O>[CH2:31]([O:21][C:20](=[O:22])[C@@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 56 %

Procedure:
N-(t-Butoxycarbonyl)-D-tryptophan (3 g; 9.868 mmol) was dissolved in acetone and an aqueous solution of potassium carbonate (2.84 g; 20.58 mmol) added followed by allyl bromide (1.55 g; 12.81 mmol). The reaction mixture was stirred for 18 h and then the acetone was substantially removed by evaporation under reduced pressure. The oily water layer that remained was acidified to approximately pH=5 with 1N-hydrochloric acid and then extracted with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate powder, filtered and evaporated under reduced pressure to give a foamy solid. The foam was further purified by column chromatography using silica gel and ethyl acetate and hexanes 2:1 v/v as eluant. In this manner, a 1.92 g yield (56%) of the desired product was obtained as an off white solid. FAB-MS:- calculated for C19H24N2O4 344; found 344 (M).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([C:16](=[C:22]([NH2:27])[C:23]([F:26])([F:25])[F:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:15])[CH3:14].[F:28][C:29]([F:36])([F:35])[C:30](OCC)=O.Cl>CCCCCC.O1CCCC1>[F:24][C:23]([F:25])([F:26])[C:22]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:13]([OH:15])[CH:14]=[C:30]([C:29]([F:36])([F:35])[F:28])[N:27]=1
Reactant: CCOC(=O)C(C(C)=O)=C(N)C(F)(F)F
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a flame dried, 3-liter, four-necked flask equipped with nitrogen inlet, low temperature thermometer, 500 ml addition funnel and mechanical stirrer was charged 91.0 g (126 ml, 0.899 mol) of diisopropylamine and 500 ml of dry tetrahydrofuran. The resulting solution was cooled to -78° C. using an acetone-dry ice bath. To this was slowly added 383 ml (0.880 mol) of 2.3M n-BuLi in hexane at such a rate that the reaction temperature was kept below -60° C. After stirring at -78° C. for 1 hours, a solution of 90.0 g (0.400 mol) of ethyl 2-acetyl-3-amino4,4,4-trifluoro-2-butenoate from Example 1 in 150 ml of dry tetrahydrofuran was added at such a rate that the reaction temperature was kept below -60° C. The reaction mixture turned yellow and a solid suspension formed. After 1 hour of stirring at -78° C., the reaction mixture was treated with 184.7 g (155 ml, 1.300 mol) of ethyl trifluoroacetate at such a rate that the reaction temperature was kept below -60° C. This reaction mixture was left at -78° C. for 1 hour, then warmed to room temperature (the yellow suspension disappeared and a brown solution was formed) and stirred for 18 hours. The resulting solution was poured into 1.5 L of 10% HCl (aq.) and extracted 3 times with methylene chloride. The combined methylene chloride layers were dried (MgSo4) and reduced in vacuo affording a brown thick oil. The residue was kugelrohr distilled at 47 Pa. The earlier fraction (pot temperature 50° C.) was discarded. The later fraction (pot temperature 80° C.) afforded 80.0 g (66%) of the pyridine product, mp 70°-77° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[N:16]1([C:22]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[C:31]([F:34])([F:33])[F:32])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[C:25]([C:31]([F:33])([F:32])[F:34])=[CH:26][CH:27]=[CH:28][C:29]=3[F:30])[CH2:17][CH2:18]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1c(F)cccc1C(F)(F)F)N1CCNCC1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3c(F)cccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(6-fluoro-2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (16.8% yield). 1H NMR (400 MHz, CDCl3) δ 8.06, 7.85, 7.57-7.55, 7.39-7.36, 7.01, 4.04-3.94, 3.86-3.79, 3.49, 3.44-3.36, 1.73-1.68, 1.52, 0.94.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=4)=[C:16]([C:17]#[N:18])[C:9]=23)[CH:7]=1.C(N(CC)CC)C.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>CN(C)C=O>[C:17]([C:16]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:25][CH3:26])[NH:14][C:15]=1[C:19]1[CH2:20][CH2:21][N:22]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:23][CH:24]=1)#[N:18]
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCNCC3)c(C#N)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)N(C)C)CC3)c(C#N)c12
Temperature: 70 °C

Procedure:
To a suspension of Example 248E (125 mg, 0.359 mmol) in N,N-dimethylformamide (6 mL) was added triethylamine (0.30 mL, 2.153 mmol) and 2-chloro-N,N-dimethylacetamide (56 mg, 0.466 mmol) and the mixture was heated at 70° C. for 3 hours. After cooling, the mixture was partitioned between ethyl acetate and sodium bicarbonate and the organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (5-20% methanol in 2:1 ethyl acetate/hexane) to provide the title compound. 1H NMR (400 MHz, DMSO-d6): δ 2.77-2.80 (m, 2H), 2.86 (t, J=5.65 Hz, 2H), 2.95 (s, 3H), 3.11 (s, 3H), 3.37 (q, J=2.75 Hz, 2H), 3.77 (s, 3H), 6.65-6.67 (m, 1H), 7.04-7.12 (m, 3H), 7.15-7.21 (m, 1H), 8.34 (d, J=4.88 Hz, 1H). MS (DCI/NH3) m/z 434 (M+H)+.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=C[CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[CH:26][CH:27]=[CH:28][C:29]=1[CH:24]([CH3:25])[CH3:23])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C(C)C)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15, 1), 251 (19), 250 (100), 163 (5), 122 (5), 121 (53), 114 (8), 104 (6),103 (6), 91 (24), 77 (14).
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:5]([CH2:6]O)=[CH:4][C:3]=1[C:14]([CH3:17])([CH3:16])[CH3:15].[ClH:18]>CCCCCC>[OH:1][C:2]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:5]([CH2:6][Cl:18])=[CH:4][C:3]=1[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: Cl
Reactant: CC(C)(C)c1cc(CO)cc(C(C)(C)C)c1O
Solvent: CCCCCC
Product: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Reaction time: 8 h

Procedure:
176 grams of 4-hydroxy-3,5-di-tert-butyl-benzyl alcohol was slurried in 350 ml of hexane. 240 cc of concentrated HCl was added to the slurry and stirred overnight. The two phases were allowed to separate and the hexane phase washed twice with water. The dried hexane was then extracted with magnesium sulfate and filtered. Rotofilm evaporation yielded 168 grams of product--a pungent yellow liquid.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].C(N(CC)CC)C.[C:13]1([C:19]2[C:28]([CH3:29])=[CH:27][C:26]3[C:21](=[C:22]([C@H:30]([OH:40])[CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(OCC)C>[C:13]1([C:19]2[C:28]([CH3:29])=[CH:27][C:26]3[C:21](=[C:22]([C@H:30]([O:40][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:31][O:32][Si:33]([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:34])[CH3:35])[CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2cccc([C@H](O)CO[Si](C)(C)C(C)(C)C)c2nc1-c1ccccc1
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc2cccc([C@@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)c2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2 ml (26 mmol) of mesyl chloride and 4 ml (27 mmol) of triethylamine are added sequentially, at 0° C., to a solution of 7 g (17.8 mmol) of 2-phenyl-3-methyl-8-(1-(S)-hydroxy-2-[tert-butyldimethylsilyloxy]ethyl)quinoline in 200 ml of ethyl ether. The solution rapidly turns cloudy and a white precipitate is formed. After stirring for one hour at ambient temperature, 150 ml of distilled water are added to the reaction medium and the aqueous phase is extracted with 3×200 ml of ethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum to provide 8.4 g of 2-phenyl-3-methyl-8-(1-(S)-methanesulfonyloxy-2-[tert-butyldimethylsilyloxy]ethyl)quinoline in the form of a colorless oil, used without purification in the following stage. (Yield: quantitative)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)[C:8](=[O:19])[CH:7]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:45][C:46]1([CH3:58])[O:50][C@H:49]([CH2:51][N:52]2[CH:56]=[CH:55][C:54]([NH2:57])=[N:53]2)[CH2:48][O:47]1>ClCCl>[CH3:45][C:46]1([CH3:58])[O:50][C@H:49]([CH2:51][N:52]2[CH:56]=[CH:55][C:54]([NH:57][C:12](=[O:14])[C@@H:11]([N:9]3[CH2:10][C:6]([O:5][C:4]4[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[C:3]=4[F:23])=[CH:7][C:8]3=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])=[N:53]2)[CH2:48][O:47]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.9 %

Procedure:
A solution of (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.75 g, 2.20 mmol) in dichloromethane (39 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.42 mL, 2.40 mmol) and 1-hydroxybenzotriazole (0.31 g, 2.29 mmol). The reaction was stirred at 25° C. for 20 min. At this time, the reaction was treated with 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.53 g, 2.68 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous ammonium chloride solution (2×50 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes) afforded (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.56 g, 49%) as a light yellow solid: HR-ES-MS m/z calculated for C25H30N4O5FCl [M+H]+ 521.1962, observed 521.1963; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.46 (br. s., 1H), 1.51-1.65 (m, 1H), 1.71-1.82 (m, 1H), 3.74 (dd, J=8.5, 5.8 Hz, 1H), 4.01 (dd, J=8.2, 6.3 Hz, 1H), 4.04-4.18 (m, 2H), 4.25 (d, J=18.5 Hz, 1H), 4.35 (dq, J=6.0, 5.8 Hz, 1H), 4.61 (d, J=18.5 Hz, 1H), 4.89 (dd, J=10.9, 4.7 Hz, 1H), 5.03 (s, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.33 (td, J=8.3, 1.3 Hz, 1H), 7.50-7.60 (m, 2H), 7.60 (d, J=2.1 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]>CO.[Pd]>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C=CC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 2 h
Yield: 73.6 %

Procedure:
3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylic acid (Example 17) (0.050 g) was dissolved in 5 ml of MeOH and combined with 0.005 g of 10% Pd/C. The reaction vessel was purged three times with N2 and then placed under a balloon of H2 gas. After 2 h, the reaction mixture was filtered and conc'd to give 0.037 g (74% yield) of a white solid. (MH+=417.30)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:11][CH2:10][C@@H:9]([NH:12][C:13]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:19])[C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of (S)-tert-butyl 1-(3-chloro-4-fluorophenyl)-2-hydroxyethylcarbamate (0.75 g, 2.59 mmol) and DCM (15 mL) at RT was added TEA (0.541 mL, 3.88 mmol) and MsCl (0.210 mL, 2.72 mmol). The reaction was stirred at RT for 1 h then poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:5) to afford 0.8 g (84%) of (S)-2-(tert-butoxycarbonylamino)-2-(3-chloro-4-fluorophenyl)ethyl methanesulfonate (224).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([NH2:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[N:20]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:21])[F:22])[CH:5]=1)[CH:19]=[CH:18]2)=[C:24]=[O:26]
Reactant: Nc1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Reaction time: 48 h

Procedure:
2-(3-(trifluoromethoxy)phenyl)quinolin-8-amine (252 mg, 0.830 mmol) in toluene (10 mL) was added a mixture of triphosgene (82 mg, 0.275 mmol) in toluene (5 mL). The mixture was stirred for 2 days to obtain 8-isocyanato-2-(3-(trifluoromethoxy)phenyl)quinoline, which was used without isolation.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+].[F:16][C:17](I)([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20]>CN(C=O)C>[F:23][C:18]([F:24])([C:19]([F:22])([F:21])[F:20])[C:17]([F:25])([F:16])[S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Sc1ccccc1-c1ccccc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)C(F)(F)C(F)(F)Sc1ccccc1-c1ccccc1
Yield: 81.4 %

Procedure:
To a solution composed of 20 ml of DMF and 2.24 g (12 mmol) of 2-mercaptobiphenyl was added 481 mg (12 mmol) of sodium hydride (60% in oil) little by little under ice cooling and stirring. Then, 1.73 ml (12 mmol) of perfluoropropyl iodide was added dropwise. The temperature of the mixture was slowly elevated to room temperature, and the mixture was stirred for 2 days. The white precipitate formed in the reaction solution was removed by filtration. Water was addd to the filtrate, and the mixture was extracted with hexane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a brown oil. It was purified by silica gel column chromatography (ethyl acetate:hexane=1:30) to give 3.46 g (87.3%) of 2-(heptafluoropropylthio)biphenyl as a colorless oil. The properties of the product were as shown below.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:17](C(OC(C)(C)C)=O)[C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5].FC(F)(F)C(O)=O>>[CH2:2]([O:3][C:4]([C:6]1[NH:17][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(OCC)cnc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2cc(OCC)cnc2[nH]1

Procedure:
This compound was prepared in analogy to Example 3, intermediate e) from 5-ethoxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester and trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.N[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>>[NH2:20][C:9]1[C:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:11][C:5]2[CH:4]=[N:3][C:2]([NH:1][CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[N:7][C:6]=2[N:8]=1
Reactant: CN1CCN(CCCCN)CC1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Product: CN1CCN(CCCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1

Procedure:
Following the procedure of Example 20, 2.0 g of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine from Example 1 was reacted with 15 mL of 1-(4-aminobutyl)-4-methyl-piperazine to give the title compound.
Reaction SMILES: COC1C=CC(C[O:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]([CH2:40][O:41][CH2:42][CH2:43][NH:44][C:45](=[O:61])[O:46][CH2:47][CH:48]4[C:60]5[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=5[C:54]5[C:49]4=[CH:50][CH:51]=[CH:52][CH:53]=5)[N:21]4[C:26]5[CH:27]=[CH:28][N:29]([S:30]([C:33]6[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=6)(=[O:32])=[O:31])[C:25]=5[N:24]=[CH:23][C:22]=34)=[CH:14][CH:13]=2)([CH3:11])[CH3:10])=CC=1.COC1C=CC(COC(C2C=CC([Mg]Br)=CC=2)(C)C)=CC=1.C1C2C(COC(NCCOCC(O)=O)=O)C3C(=CC=CC=3)C=2C=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl.FC(F)(F)C([O-])=O.[Hg+2].FC(F)(F)C([O-])=O.O>[OH:8][C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:19]=[C:20]([CH2:40][O:41][CH2:42][CH2:43][NH:44][C:45](=[O:61])[O:46][CH2:47][CH:48]3[C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][C:54]=4[C:55]4[C:60]3=[CH:59][CH:58]=[CH:57][CH:56]=4)[N:21]3[C:26]4[CH:27]=[CH:28][N:29]([S:30]([C:33]5[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=5)(=[O:32])=[O:31])[C:25]=4[N:24]=[CH:23][C:22]=23)=[CH:16][CH:17]=1)([CH3:10])[CH3:11]
Reactant: COc1ccc(COC(C)(C)c2ccc(-c3nc(COCCNC(=O)OCC4c5ccccc5-c5ccccc54)n4c3cnc3c4ccn3S(=O)(=O)c3ccc(C)cc3)cc2)cc1
Agent: COc1ccc(COC(C)(C)c2ccc([Mg]Br)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C(O)COCCNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)nc(COCCNC(=O)OCC4c5ccccc5-c5ccccc54)n23)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 45 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl 2-((3-(4-(2-(4-methoxybenzyloxy)propan-2-yl)phenyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)methoxy)ethylcarbamate (0.077 g, 0.089 mmol, prepared using AF from Example #2, Step B cyano intermediate with ((4-(2-(4-methoxybenzyloxy)propan-2-yl)phenyl)magnesium bromide [NOVEL], AG, J.1 with 2-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethoxy)acetic acid [Chem Impex] and L.1 with mercury(II) trifluoroacetate) in DCM (0.94 mL) and Water (0.05 mL) was added DDQ (0.030 gg, 0.134 mmol). The mixture was stirred at rt for about 45 min. The mixture was directly purified by flash chromatography (12 g silica gel column, 35 to 100% EtOAc/heptane) to give (9H-fluoren-9-yl)methyl 2-((3-(4-(2-hydroxypropan-2-yl)phenyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)methoxy)ethylcarbamate (0.03 g, 45%): LC/MS (Table 2, Method b) Rt=2.90 min.; MS m/z: 742 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]2[N:28]=[CH:29][S:30][C:26]=2[CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[S:30]1[C:26]2[CH:25]=[C:24]([NH:23][C:2]3[CH:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12]4[O:13][C:14]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[N:15][N:16]=4)=[CH:4][N:3]=3)[CH:32]=[CH:31][C:27]=2[N:28]=[CH:29]1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nnc(-c2ccccc2)o1
Reactant: Nc1ccc2ncsc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(-c2ccccc2)o1
Temperature: 110 °C

Procedure:
To solution of 2-chloro-N-isopropyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-4-amine (200 mg, 0.6 mmol) in dioxane (10 mL): H2O (2 mL), 6-amino benzothiazole (0.63 mmol, 1 equiv.), xanthphos (0.2 mmol, 0.4 equiv.) and Na2CO3 (2.5 mmol, 4 equiv.) were added and degassed for 10 min. To the reaction mixture Pd2(dba)3 (0.2 mmol, 0.4 equiv.) was added and degassed again for 10 min. It was then heated at 110° C. for overnight. The reaction mass was cooled and filtered through small pad of celite. The filtrate obtained was concentrated to provide crude material. The crude material was purified by column chromatography through silica gel and MeOH: DCM as eluent. The material obtained was further purified by prep. HPLC to afford N2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine.