Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:22][O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:24]([O:23][CH3:22])=[O:33])=[CH:26][CH:27]=2)[C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Cn1c(Nc2cc(Cl)cc(Cl)c2)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(c2cc(Cl)cc(Cl)c2)c2nc3ccccc3n2C)cc1
Reaction time: 0.25 h

Procedure:
To the title compound from Example 223 Step A (0.21 mmol, 60 mg) and NaH (0.24 mmol, 6 mg of a 60% slurry in mineral oil) was added 0.5 mL of DMF (gas evolution). After 15 min, methyl-4-(bromomethyl)benzoate (0.24 mmol, 55 mg) was added and the reaction mixture was allowed to stand at ambient temperature overnight. The mixture was partitioned between DCM and NaHCO3. The organic phase was collected and the aqueous phase was extracted 2× with DCM. After 30 min the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica eluting with 2% MeOH/DCM. The product was further purified by reverse phase HPLC (Condition B). The combined HPLC fractions were neutralized with saturated NaHCO3 and extracted with DCM. The organic phase was dried over MgSO4 and concentrated under reduced pressure to afford the product as a white solid. 1H NMR (500 MHz, d6-DMSO) δ 7.94 (d, 2H), 7.68 (d, 2H), 7.61 (d, 1H), 7.52 (d, 1H), 7.21-7.29 (overlapping m, 2H), 7.10 (t, 1H), 6.79 (d, 2H), 5.27 (s, 2H), 3.83 (s, 3H), 3.50 (s, 3H). MS (ESI): m/z 440 (M+H). HPLC A: 2.16 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.[O:19]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C>C(O)C>[O:19]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])[CH:3]=2)=[CH:31][CH:32]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cccc(Nc2cc(Cl)ncn2)c1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 100 °C
Yield: 63.8 %

Procedure:
To a stirring solution of methyl 3-(6-chloropyrimidin-4-ylamino)benzoate (1.0 g, 3.8 mmol) and 4-phenoxy aniline (0.703 g, 3.8 mmol) in ethanol (5 mL) was added acetic acid (0.22 mL) and the reaction mixture was heated at 100° C. for 48 h. The reaction mixture was cooled, ethanol was removed under reduced pressure and the residue was dissolved in ethyl acetate (50 mL). It was washed with NaHCO3 solution (5 mL) and brine (5 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to yield methyl 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzoate (1 g, 66%) as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:47])([F:46])[C:4]([F:45])([F:44])[C:5]([F:43])([F:42])[C:6]([F:41])([F:40])[C:7]([F:39])([F:38])[C:8]([F:37])([F:36])[C:9]([F:35])([F:34])[C:10]([F:33])([F:32])[CH2:11][O:12][C:13]1([F:31])[C:26]([F:27])=[C:25]([F:28])[C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[C:15]([F:29])[CH:14]1[F:30].[N+:48]([C:51]1[CH:56]=[C:55]([N+:57]([O-:59])=[O:58])[CH:54]=[CH:53][C:52]=1Cl)([O-:50])=[O:49]>CN1C(=O)CCC1>[N+:48]([C:51]1[CH:56]=[C:55]([N+:57]([O-:59])=[O:58])[CH:54]=[CH:53][C:52]=1[O:1][CH2:2][C:3]([F:46])([F:47])[C:4]([F:44])([F:45])[C:5]([F:42])([F:43])[C:6]([F:40])([F:41])[C:7]([F:38])([F:39])[C:8]([F:36])([F:37])[C:9]([F:34])([F:35])[C:10]([F:32])([F:33])[CH2:11][O:12][C:13]1([F:31])[C:14]([F:30])=[C:15]([F:29])[C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[C:25]([F:28])[CH:26]1[F:27])([O-:50])=[O:49]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C(C1=C(F)C(F)C(F)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)C(F)=C1F)c1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(C1=C(F)C(F)C(F)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])C(F)=C1F)c1ccccc1

Procedure:
A solution of 4-(10-Hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-hexadecafluorodecyloxy)-2,3,4,5,6-pentafluorobenzophenone(7.14 g), 2,4-dinitrochlorobenzene (2.42 g) potassium carbonate (2.76 g) and NMP (15 mL) is heated to 75-80° C. for 24 hrs. The solution is further processed as described in example 2 to give 4-[10-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-hexadecafluorodecyloxy]-2,3,4,5,6-pentafluorobenzophenone.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:9]1([C:2]2[O:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccc(Br)o1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCc1ccc(-c2ccccc2)o1
Temperature: 80 °C
Yield: 34.6 %

Procedure:
The 5-bromo-2-hydroxymethylfuran prepared in Example 327A (1.012 g, 5.72 mmol) was dissolved in 10 mL of DMF and PdCl2 (PPh3)2 (401 mg, 0.57 mmol) was added followed by phenylboronic acid (1.39 g, 11.4 mmol) and Cs2CO3 (3.71 g, 11.4 mmol) and the reaction was heated at 80° C. under N2 for 12 hours. The reaction mixture was taken up in ethyl acetate and washed with water (3×) and brine (3×), dried over Na2SO4, filtered and evaporated to a brown oil that was purified by flash chromatography (50% ethyl acetate-hexanes) to give the desired compound (345 mg, 35%) as an oil.
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:5]=2[C:4](=[O:14])[NH:3][CH:2]=1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1([CH2:26][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)[CH2:25][O:24]1.C[O-].[Na+]>C(O)(C)(C)C>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]([OH:24])([CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[CH2:25][N:3]1[C:4](=[O:14])[C:5]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[S:7][C:6]=2[N:1]=[CH:2]1
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Reactant: O=c1[nH]cnc2sc3c(c12)CCCC3
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=c1c2c3c(sc2ncn1CC(O)(Cn1cncn1)c1ccc(F)cc1F)CCCC3
Yield: 60 %

Procedure:
5,6,7,8-Tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A09) (1.0 g, 4.8 mmole), 1[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole of the Formula (5) (1.38 g, 5.8 mmole) and sodium methoxide (0.31 g, 5.8 mmole), were taken in two neck round bottom flask under inert atmosphere, dry t-butanol (30 ml) was added to the above reaction mixture and the mixture was stirred under reflux for 12 hours. t-Butanol was removed on rotavapor, water (20 ml) was added to the reaction mixture, the compound from the reaction mixture was extracted with ethyl acetate (3×20 ml), dried, concentrated and purified by column chromatography to obtain the pure 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one (1-A09) (1.29 gm, 60%). 1HNMR (CDCl3, 200 MHz): 1.74-1.96 (m, 4H), 2.71-2.81 (m, 2H), 2.90-3.02 (m, 2H), 4.18 (d, J=14 Hz, 1H), 4.55 (d, J=14 Hz, 1H), 4.70 (d, J=14 Hz, 1H), 4.77 (d, J=14 Hz, 1H), 6.29 (bs, 1H), 6.72-6.92 (m, 2H), 7.51-7.62 (m, 1H), 7.85 (s, 2H), 8.13 (s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16](=[O:22])[C:17]([O:19]CC)=[O:18])=[C:10]([O:24][CH2:25][CH2:26][O:27][CH3:28])[C:9]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.CO.[OH-].[Na+]>O>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16](=[O:22])[C:17]([OH:19])=[O:18])=[C:10]([O:24][CH2:25][CH2:26][O:27][CH3:28])[C:9]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(Cc2ccccc2)c(OC)c1OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1c(C(=O)CC(=O)C(=O)O)ccc(Cc2ccccc2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 200 mL round bottomed flask with a stirring bar and a nitrogen inlet was added ethyl 4-(benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyrate (1.48 g, 3.57 mmol), THF (30 mL), methanol (30 mL), and sodium hydroxide solution (18 mL of a 1 N solution in water, 18 mmol). This mixture was stirred 2 h at ambient temperature. The organic solvents were removed in vacuo and the aqueous residue was diluted with 30 mL of water. This solution was washed with ethyl ether (2×50 mL) then acidified with 1N HCl. This mixture was extracted with ethyl ether (100 mL). The ether solution was washed with water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave a yellow oil. This material was crystallized by dissolving in 1:1 ether-hexane (−5mL) and storing in a freezer over night. The crystalline product was collected by filtration on a frit and dried in vacuo at ambient temperature to give 4-(benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyric acid as yellow needles. MP: 83-85° C. Anal. Calc'd for C21H22O7: C, 65.28; H, 5.74; Found: C, 65.28; H, 6.05. 1H NMR (CDCl3): δ3.39 (s, 3H); 3.71 (t, j=4 Hz, 2H); 3.82 (s, 3H); 3.96 (s, 2H); 4.21 (t, j=4 Hz, 2H); 6.90 (d, j=2Hz, 1H); 7.28 (m, 6H); 9.60 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=C(C2CCCC(=NO)C=2)C=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].Cl>C(O)(=O)C>[C:28]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:30])[CH3:29]
Reactant: Nc1cccc(-c2cccnc2)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: ON=C1C=C(c2cccnc2)CCC1
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2cccnc2)c1
Reaction time: 3 h

Procedure:
D-2. 3-(3-Aminophenyl)pyridine-- To a mixture containing 28.9 g. of 3-(3-pyridinyl)-2-cyclohexen-1-one oxime, 42 ml. of acetic acid and 42 ml. of acetic anhydride was passed gaseous hydrogen chloride whereupon the temperature rose to about 120° C. The hydrogen chloride was passed continuously into the reaction mixture until the temperature fell to about 50° C. The reaction mixture was allowed to stand for 3 hours and then concentrated in vacuo to yield, as a glassy material, 3-(3-acetamidophenyl)pyridine. To this material was added 100 ml. of water and 25 ml. of concentrated hydrochloric acid and the resulting mixture was refluxed for 16 hours and concentrated in vacuo to yield a yellow solid. The solid was taken up in water and the solution was made alkaline with 35% aqueous sodium hydroxide solution. The alkaline solution was extracted three times with ethylene dichloride. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield an oil. The oil was distilled under reduced pressure, collecting the fraction boiling at 141°-145° C. at 0.15 mm. to yield, first as a yellow oil which crystallized on cooling, 17.7 g. of 3-(3 -aminophenyl)pyridine, m.p. 72°-74° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:9](=[O:21])[CH2:8][CH2:7]2)([O-])=O.O.NN>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)[C:9](=[O:21])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCN1CCCC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)CCC(=O)N2CCN1CCCC1

Procedure:
To solution of 6-nitro-1-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (205 mg, 0.709 mmol) in 5 mL methanol was added to Raney Nickel (slurry in H2O, 50 mg) in a reaction vial. The suspension was treated with hydrazine hydrate (220 μL, 7.09 mmol) and heated at reflux for 2 hours and then filtered through a pad of celite. The celite pad was rinsed with 10 mL methanol. The filtrate was concentrated and the resulting product was subjected to flash silica gel chromatography using 2.5% 2M NH3 in MeOH/CH2Cl2 to afford a yellow oil. Yield: 180 mg (98%). 1H NMR (CDCl3) δ: 6.89 (d, J=8.4 Hz, 1H), 6.56 (dd, J=2.7, 8.4 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 4.04 (t, J=7.5 Hz, 2H), 2.81-2.76 (m, 2H), 2.71-2.66 (m, 2H), 2.63-2.56 (m, 6H), 1.81-1.77 (m, 4H). MS (ESI): 260.2 (M+1, 100%).
Reaction SMILES: Br[C:2](=[C:5]([NH:13][CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[C:3]#[N:4].[F:15][C:16]([F:21])([F:20])[C:17](=O)[CH3:18]>C(O)(=O)C.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]2[N:13]([CH3:14])[C:17]([C:16]([F:21])([F:20])[F:15])=[CH:18][C:2]=2[C:3]#[N:4])=[CH:7][CH:8]=1
Reactant: CC(=O)C(F)(F)F
Reactant: CNC(=C(Br)C#N)c1ccc(Cl)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(C#N)c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A solution of α-bromo-p-chloro-β-(methylamino)cinnamonitrile, (E)- or (Z)- (5.43 g, 0.02 mol) and trifluoroacetone (3.36 g, 2.7 mL, 0.03 mol) in acetic acid is heated at 80° C. for 1-2 hours, heated at 100° C. overnight, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain a gum. The gum is flash chromatographed using silica gel and a 15% ethyl acetate in heptane solution to give the title product as a yellow solid (1.7 g, mp 129°-131° C.) which is identified by 1H and 19FNMR spectral analyses.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH3:11][N:12]1C(=O)O[C:15](=[O:16])[C:14]2=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=[C:13]12>>[CH3:11][NH:12][C:13]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:14]=1[C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:16]
Reactant: Oc1n[nH]c2ccccc12
Reactant: Cc1ccc2c(c1)c(=O)oc(=O)n2C
Product: CNc1ccc(C)cc1C(=O)n1nc(O)c2ccccc21
Yield: 40.5 %

Procedure:
1H-Indazol-3-ol was reacted with N-methyl-5-methylisatoic anhydride according to the general procedue A above and afforded the desired amine as yellow solid in 40.5% yield; m.p. 173°-175° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3](Cl)[CH2:4][C:5](=[O:9])[CH2:6][CH2:7][CH3:8].[SH:11][CH2:12][CH2:13]O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:6]([C:5]1[O:9][CH2:13][CH2:12][S:11][C:4]=1[CH2:3][CH2:2][Cl:1])[CH2:7][CH3:8]
Reactant: OCCS
Reactant: CCCC(=O)CC(Cl)CCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCC1=C(CCCl)SCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 0.056 mole (10 g.) of 1,2-dichloro-4-heptanone and 0.06 mole (5 g.) 2-mercaptoethanol was stirred in 200 ml toluene; 0.06 mole (6 g.) triethylamine was added dropwise. The mixture was stirred at room temperature overnight, then washed with dilute hydrochloric acid and refluxed with 0.5 mole PTS, using a Dean-Stark trap to remove water for 7 hours. The PTSA solution was washed with 5% sodium bicarbonate, dried, filtered and the solvent was removed. The product was distilled; bp 80°-85°/0.05 mm. Yield 23%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:20])[C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH3:20])[C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: Cc1cc(OCCCCCl)cc2c1NC(=O)OC2(C)C
Product: CC(=O)Nc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1.[CH3:27][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH:28]([CH3:35])[CH3:27])[CH2:15][CH2:14]2)[C:10]=1[CH3:11]
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Reactant: CC(C)CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)CCCC(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine (42 mg, 0.1 mmol), 5-methyl-hexanoic acid (0.12 mmol, 1.2 eq), HATU (0.12 mmol, 1.2 eq), and triethylamine (0.2 mmol, 2 eq) were dissolved in DMF (1 mL), and then stirred at room temperature for 1 hour. The crude was filtered and then purified via prep-LCMS 5-95% to provide Compound C121 as a white powder (28.2 mg, 57%). Exact mass calculated for C24H32FN3O5S 493.2, found LCMS (ESI) mf/z 494.5 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:34][CH3:35])=[C:18]([CH:25]4[CH2:28][N:27]([C@@H:29]([CH3:33])[C:30](O)=[O:31])[CH2:26]4)[C:19]([CH3:24])=[C:20]([C:22]#[N:23])[CH:21]=3)[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12.[Cl-].C[NH3+].[CH2:39]([N:41](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:34][CH3:35])=[C:18]([CH:25]4[CH2:26][N:27]([C@@H:29]([CH3:33])[C:30]([NH:41][CH3:39])=[O:31])[CH2:28]4)[C:19]([CH3:24])=[C:20]([C:22]#[N:23])[CH:21]=3)[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN([C@@H](C)C(=O)O)C1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: CNC(=O)[C@H](C)N1CC(c2c(C)c(C#N)cc(C(C)n3nc(C(F)F)c4c(N)ncnc43)c2OC)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (2S)-2-[3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-cyano-2-methoxy-6-methylphenyl)azetidin-1-yl]propanoic acid (30 mg, 0.06 mmol), methylammonium chloride (6.6 mg, 0.098 mmol) and triethylamine (18 μL, 0.13 mmol) in N,N-dimethylformamide (0.3 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (43 mg, 0.098 mmol). The resulting mixture was stirred for 3 h at room temperature. The mixture was diluted with acetonitrile, filtered, and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 4.7 mg (10%, 3 steps) of the desired product. The product was isolated as mixture of diastereomers. LCMS calculated for C24H29F2N8O2 (M+H)+: m/z=499.2; Found: 499.1.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](Cl)=[O:8])[N:6]=1.ClC1SC=C(C(O)=O)N=1.S(Cl)(Cl)=O.[Br:23][C:24]1[CH:30]=[C:29]([C:31]([F:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])[CH:28]=[C:27]([C:41]([F:44])([F:43])[F:42])[C:25]=1[NH2:26]>>[Br:23][C:24]1[CH:30]=[C:29]([C:31]([F:40])([C:32]([F:34])([F:35])[F:33])[C:36]([F:37])([F:39])[F:38])[CH:28]=[C:27]([C:41]([F:42])([F:43])[F:44])[C:25]=1[NH:26][C:7]([C:5]1[N:6]=[C:2]([Cl:1])[S:3][CH:4]=1)=[O:8]
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(Cl)c1csc(Cl)n1
Agent: O=C(O)c1csc(Cl)n1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1csc(Cl)n1

Procedure:
According to the method of 4-3 of Example 4, a target compound was prepared from 2-chlorothiazole-4-carbonylchloride prepared from 2-chlorothiazole-4-carboxylic acid and thionyl chloride, and 2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline obtained in 1-2 of Example 1.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([C:14]([OH:16])=O)[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([C:14]([N:35]3[CH2:34][CH2:33][CH:32]([C:26]4[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:31])[CH2:37][CH2:36]3)=[O:16])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(Cl)c1C1CCNCC1
Reactant: Cc1cccc2c1CCC(C(=O)O)CC2=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cccc2c1CCC(C(=O)N1CCC(c3c(Cl)cccc3Cl)CC1)CC2=O
Temperature: 25 °C
Yield: 71 %

Procedure:
1 g (4.58 mmol) of (±)-1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylic acid was dissolved in 40 mL of dry CH2Cl2 and 1.2 mL (13.74 mmol) of oxalyl chloride were added dropwise at 0° C. under a nitrogen atmosphere. The solution was allowed to warm to room temperature overnight, then the solvent and the excess oxalyl chloride were removed in vacuo. The resulting acyl chloride was dissolved in 20 mL of dry CH2Cl2 and added to a solution of 1.22 g (4.58 mmol) of 4-(2,6-dichloro-phenyl)-piperidine hydrochloride and 1.91 mL (13.74 mmol) of triethylamine in 30 mL of dry CH2Cl2 at 0° C. The reaction mire was allowed to warm to room temperature overnight, water was added, the organic phase was collected, washed with 1 N HCl solution and dried. The solvent was removed in vacuo and the resulting crude product was purified by flash chromatography, eluting with a mixture Et2O/Hexane 8:2 respectively, yielding 1.4 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.C=O.O.[C:29]([O:32][CH2:33]C)(=O)[CH3:30]>C(O)C>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:24]=[CH:25][C:2]([NH:1][CH2:33][O:32][CH2:29][CH3:30])=[N:3][CH:4]=2)=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccc(C(=O)NCc2ccc(OCc3ccccc3)cc2)cn1
Reactant: CCOC(C)=O
Agent: C=O
Solvent: CCO
Solvent: O
Product: CCOCNc1ccc(C(=O)NCc2ccc(OCc3ccccc3)cc2)cn1
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of the resulting 6-amino-N-(4-benzyloxy-benzyl)-nicotinamide (200 mg, 0.556 mmol) in ethanol (10 mL) were added 5,5-dimethylimidazophospho-2,4-dione (85 mg, 0.66 mmol) and 37% formaldehyde aqueous solution (1 mL), and the solution was stirred for 1 hour under reflux. Water and ethyl acetate were added to the reaction solution, which was then partitioned, and the organic layer was washed twice. NH silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (ethyl acetate), and the title compound (95 mg, 0.243 mmol, 40%) was obtained as a white solid.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[C:18]1([C:24]2[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[S:26][N:25]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:28]=2)[CH2:30][CH2:31]1)=[O:9])([CH3:2])[CH3:3]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 83 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropylsulfanyl-5-methanesulfonyl-benzoic acid (Example A22) and 3-phenyl-5-piperazino-1,2,4-thiadiazole. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as an off-white solid (yield 83%). MS (m/e): 503.1 (M+H+, 100%).