Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:16]=[C:15]3[C:10]([O:11][CH2:12][CH:13]=[CH:14]3)=[C:9]([CH3:17])[C:4]=2[O:5][C:6](=[O:8])[CH:7]=1.C1CCCCC=1>[Pd].C(O)C>[CH3:1][C:2]1[C:3]2[CH:16]=[C:15]3[C:10]([O:11][CH2:12][CH2:13][CH2:14]3)=[C:9]([CH3:17])[C:4]=2[O:5][C:6](=[O:8])[CH:7]=1
Reactant: Cc1cc(=O)oc2c(C)c3c(cc12)C=CCO3
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Cc1cc(=O)oc2c(C)c3c(cc12)CCCO3
Yield: 39.5 %

Procedure:
A mixture of 4,10-dimethyl-2H,8H-benzo[1,2-b;5,4-b']dipyran-2-one (100 mg, 0.44 mmoles), cyclohexene (0.5 ml, 4.94 mmoles) and palladium on activated carbon (10%, 50 mg) in ethanol (25 ml) was refluxed for 5 hr. The mixture was cooled, filtered and the solvent removed under reduced pressure. The residue was recrystallized from benzene/cyclohexene to afford colorless needles of 6,7-dihydro-4,10-dimethyl-2H,8H- benzo[1,2-b;5,4-b']dipyran-2-one (40 mg, 40%), mp 162°-163° C.; 1H NMR 1.93, mult, 2H, H7 ; 2.11, s, 3H, C10 -- Me; 2.24, d, J=1.0 Hz, 3H, C4 --Me; 2.75, t, J=6.5 Hz, 2H, H6 ; 4.20, t, J=5.2 Hz, 2H, H8 ; 5.94, d, J=1.0 Hz, 1H, H3 ; 6.99, s, 1H, H5. 13C NMR 7.88, q, C10 --Me; 18.52, q, C4 --Me; 21.85, 24.86, two t, C6 and C7 ; 66.90, t, C8 ; 111.29, d, C3 ; 112.73, 112.84, two d, C5a and C10 ; 118.31, s, C4a ; 122.078, d, C5 ; 150.92, s, C9a ; 152.55, s, C4 ; 155.74, s, C10a ; 161.54, s, C2.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:14]([C@@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]2)[C:13]2[CH:25]=[C:26]([CH2:29]O)[CH:27]=[CH:28][C:12]=2[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:35][C:36]1([CH3:44])[CH2:41][CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[NH:37]1>C(Cl)Cl>[C:1]([NH:9][C:10]1[N:14]([C@@H:15]2[CH2:16][CH2:17][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH2:20]2)[C:13]2[CH:25]=[C:26]([CH2:29][N:37]3[C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][CH2:41][C:36]3([CH3:44])[CH3:35])[CH:27]=[CH:28][C:12]=2[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: COC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccccc3)nc3ccc(CO)cc32)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccccc3)nc3ccc(CN4C(C)(C)CCCC4(C)C)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
cis-Methyl 4-(2-benzamido-6-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (0.05 g, 0.123 mmol) was suspended in DCM (1.2 mL) and cooled to 0° C. under nitrogen atmosphere. To this mixture was added thionyl chloride (0.292 g, 2.454 mmol), and the mixture was stirred for 30 minutes. The resulting mixture was concentrated under reduced pressure and dried under high vacuum. The residue was suspended in 2 mL of DMSO and cooled in an ice bath under nitrogen atmosphere. To this mixture was added 2,2,6,6-tetramethylpiperidine (0.173 g, 1.227 mmol) dropwise, and the reaction was stirred in an ice bath for 30 minutes and at RT for another 30 minutes. The reaction mixture was diluted with DCM (20 mL) and washed with water (10 mL). The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The residual yellow oil was triturated with 10% water/MeOH to afford cis-methyl 4-(2-benzamido-6-((2,2,6,6-tetramethylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (20 mg, 30.8% yield). MS m/z=531.2 [M+H]. Calc'd for C32H42N4O3: 530.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 12H) 1.54-1.73 (m, 6H) 1.73-1.99 (m, 4H) 2.25-2.41 (m, 2H) 2.46-2.54 (m, 2H) 2.84-3.02 (m, 1H) 3.81 (s, 3H) 3.93 (s, 2H) 4.73-5.08 (m, 1H) 7.25 (d, J=8.31 Hz, 1H) 7.39-7.62 (m, 4H) 7.74 (s, 1H) 8.23-8.35 (m, 2H) 12.76 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([C:37](=[O:57])[C@@H:38]([NH:46][CH2:47][C:48]2[CH:49]=[C:50]3[C:54](=[CH:55][CH:56]=2)[NH:53][CH:52]=[CH:51]3)[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:39]([C@H:38]([N:46]([CH2:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][CH:52]=[CH:51]2)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=1)[C:37]([N:34]1[CH2:33][CH2:32][N:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:36][CH2:35]1)=[O:57])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C([C@H](Cc1ccccc1)NCc1ccc2[nH]ccc2c1)N1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: O=C([C@H](Cc1ccccc1)N(Cc1ccc2[nH]ccc2c1)C(=O)C=Cc1ccc(C(F)(F)F)cc1)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
In an inert atmosphere, trans-4-(trifluoromethyl)cinnamic acid (34 mg, 0.156 mmol) was dissolved in DCM (3 mL) and 1-chloro-N,N,2-trimethylpropenylamine (24 mg, 0.182 mmol) was added at rt. The reaction mixture was stirred for 30 min followed by the addition of 1-(4-benzyl-piperazin-1-yl)-2-[(1H-indol-5-ylmethyl)-amino]-(S)-3-phenyl-propan-1-one (59 mg, 0.13 mmol). Stirring was continued at rt for 3 h. The solvents were evaporated under reduced pressure and the residue was directly purified by prep. HPLC to give 33 mg (39%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(1H-indol-5-ylmethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=0.96 min; [M+H]+=651.24.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[C:5]2[CH2:18]C(C1OCCO1)C.Cl.[CH2:27]([OH:29])[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[C:5]2[CH2:18][C:27](=[O:29])[CH3:28]
Reactant: CC(Cc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12)C1OCCO1
Reactant: CCO
Agent: Cl
Product: CC(=O)Cc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12

Procedure:
A mixture of 14g of 5-chloro-3-[2(1,3-dioxolan-2-yl)propyl]-1-(4-fluorophenyl)indole, 112 ml of 96% ethyl alcohol, and 12 ml of 6N hydrochloric acid are heated to reflux for 30 minutes. The reaction mixture is concentrated then dissolved in water and extracted with ether. The organic phase is washed in water, dried, concentrated and then distilled.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a stirred solution of 2-bromo-5-iodobenzoic acid (150 g, 458 mmol) in dichloromethane (1500 ml) was added DMF (2.0 ml) followed by oxalylchloride (58.2 ml, 688 mmol) at 0° C. in drop wise fashion over the period of 30 min. After complete addition, the reaction mixture was stirred at room temperature for 3 h. Volatiles were evaporated under reduced pressure to give 2-bromo-5-iodo-benzoyl chloride (−158 g). The crude product was used for the next step immediately. (Note: The product should not be exposed to air).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:1][C:2]1[CH:11]=[C:10]([O:12][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a solution of methyl 2,4-dihydroxybenzoate (388 mg, 2.0 mmol) in dimethylformamide (5 mL) was added triethylamine, Et3N, (0.556 mL, 4.0 mmol) followed by trityl chloride (557.5 mg, 2.0 mmol) and 4-dimethylaminopyridine (DMAP) (20 mg). The reaction mixture was kept on stirring at room temperature overnight, poured into a mixture of ice-water, the white precipitate was collected by filtration. This precipitate was subjected to silica gel flash chromatography (0-5% ethyl acetate in petroleum ether) to give the subtitled compound (350 mg).
Reaction SMILES: [CH3:1][CH:2]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]3)[CH2:6][CH2:5]1.[CH3:28][C:29]1[S:30][C:31]([C:35](O)=[O:36])=[C:32]([CH3:34])[N:33]=1>>[CH3:28][C:29]1[S:30][C:31]([C:35]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([CH:2]([CH3:1])[CH2:3][N:4]3[CH2:5][CH2:6][N:7]([C:10]4[CH:19]=[CH:18][CH:17]=[C:16]5[C:11]=4[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]5)[CH2:8][CH2:9]3)[CH:22]=2)=[O:36])=[C:32]([CH3:34])[N:33]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: Cc1ccc2c(N3CCN(CC(C)c4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CC(C)c4cccc(NC(=O)c5sc(C)nc5C)c4)CC3)cccc2n1
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield according to the general procedure for the preparation of amides (Method C) starting from 3-{1-methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D21) and 2,4-dimethyl-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C([NH:35][C@H:36]([C:45]([OH:47])=[O:46])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([NH:35][C@H:36]([C:45]([OH:47])=[O:46])[CH2:37][C:38]2[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=2)=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: O=C(O)[C@H](Cc1ccc(O)cc1)NCc1ccccc1
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(CCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)=C(C)C1=O
Yield: 20.6 %

Procedure:
Using p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6yl)propionate (187 mg, 0.5 mmol) and O benzyl-L-tyrosine (136 mg, 0.5 mmol) and following the procedure of Example 4, there was obtained 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionyl-L-tyrosine (43 mg), melting at 170° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[C:31]([F:44])[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:33]=[CH:34][C:29]([O:28][C:27]4[CH:45]=[CH:46][CH:47]=[C:48]([F:49])[C:26]=4[F:25])=[CH:30][C:31]=3[F:44])[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3F)cc2F)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3F)c3c(N)ncnc32)C1
Yield: 51.1 %

Procedure:
A solution of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.8 g, 6.16 mmol, 1.0 eq), 2-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.7 g, 6.16 mmol, 1.0 eq), Pd(PPh3)4 (0.28 g, 0.08 mmol, 0.07 eq) and Na2CO3 (1.7 g, 15.4 mmol, 2.5 eq) in dioxane/H2O (40/10 mL) was stirred at 90° C. overnight. The reaction mixture was concentrated and purified by Pre-TLC to afford (R)-tert-butyl 3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (1.7 g, 51.1% yield).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23].C(Cl)CCl>ClCCl>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:26](=[O:27])[CH2:25][NH:24][C:22](=[O:23])[C:21]2[CH:29]=[CH:30][CH:31]=[C:19]([C:18]([F:17])([F:33])[F:32])[CH:20]=2)[C@H:11]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 77.5 %

Procedure:
(2S,4R)-4-(Benzyloxy)-2-isopropylpyrrolidine (0.410 g, 1.90 mmol) was dissolved in dichloromethane (30 mL) under nitrogen. (3-Trifluoromethyl-benzoylamino)-acetic acid (0.462 g; 1.90 mmol) was added followed by EDC (0.394 g, 2.06 mmol) and the mixture was stirred at room temperature-overnight. LC/MS revealed the reaction was not yet complete. More (3-Trifluoromethyl-benzoylamino)-acetic acid (0.12 g, 0.48 mmoles) and more EDC (0.30 g, 1.6 mmoles) were added and stirring continued for 3 hours at room temperature, then at reflux for 1.5 hours. The mixture was chromatographed on silica gel eluting with 30% ethyl acetate/hexane to provide 0.66 g (79%) of the coupled product as a colorless oil. LC/MS (M+H)+ m/z=449.2; 1H NMR (CDCl3) δ 8.03 (m, 1H), 7.76 (m, 1H), 7.58 (m, 2H), 7.34 (m, 5H), 4.52 (m, 2H), 4.03-4.34 (m, 4H), 3.65 (m, 1H), 3.48 (m, 1H), 2.54 (m, 1H), 2.12 (m, 1H), 1.92 (m, 1H), 0.92 (d, 3H), 0.77 (d, 3H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:12][NH2:13]>C1COCC1.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:13][CH3:12])[S:3][C:4]=2[CH:10]=1
Reactant: CN
Reactant: Clc1ccc2nc(Cl)sc2c1
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dichlorobenzo[d]thiazole (2 g, 10 mmol) in 10 mL THF was added 25% MeNH2 in water (3 mL) dropwise. After the addition complete, the reaction mixture was stirred at room temperature overnight. Filter off the product and washed with methanol. Drying in vacuo to yield 1.5 g of the desired compound. LC-MS: m/z 204.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O.[CH3:21][C:22]1[CH:27]=[C:26]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH:24][N:23]=1.CS(C)=O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([OH:20])=[O:19])[CH:6]=[CH:7][C:8]=1[C:26]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:21])[CH:27]=1
Reactant: COc1cc(CC(=O)O)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)O)ccc1-c1ccnc(C)c1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To the mixture of 2-(3-methoxy-4-(trifluoromethylsulfonyloxy)phenyl)acetic acid 182-2 (590 mg, 1.9 mmol) and 2-methyl-4-(tributylstannyl)pyridine (730 mg, 1.9 mmol) in DMF (2.0 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33 mg, 0.04 mmol). The reaction was stirred at 110° C. for 20 hours. After cooling down to room temperature, the reaction mixture was diluted into DMSO and purified by reverse-phase HPLC to give 2-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)acetic acid 182-3. MS m/z 258.1 (M+1).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([CH:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)[CH:11]=[CH:12][C:13]=1[O:14][C:15]([F:18])([F:17])[F:16]>O>[F:7][C:8]1[CH:9]=[C:10]([CH:19]2[CH2:24][CH2:23][CH:22]([CH:2]=[O:4])[CH2:21][CH2:20]2)[CH:11]=[CH:12][C:13]=1[O:14][C:15]([F:18])([F:17])[F:16]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC(c2ccc(OC(F)(F)F)c(F)c2)CC1
Agent: [K+]
Solvent: O
Product: O=CC1CCC(c2ccc(OC(F)(F)F)c(F)c2)CC1
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To dried MTP 10.0 g (29.2 mmol), THF 100 ml was added, and potassium-t-butoxide 3.30 g (29.4 mmol) was added. The mixture was stirred for about one hour. To the reactant, a Th solution (50 ml) of the above 4-(3-fluoro-4-trifluoromethoxyphenyl)cyclohexanone 6.0 g (23.1 mmol) was added dropwise, and the mixture was stirred for 2 hours. Water 150 ml was added to the reactant, the product was extracted with diethylether. The extract was washed with a sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene). The resulting purified material was stirred in mixture solvent of 3N-hydrochloric add 200 ml and acetone 200 ml for 5 hours, and the product was extracted with toluene. The extract was washed with a saturated sodium bicarbonate aqueous solution and then with water, and dried over anhydrous magnesium sulfate. Toluene was distilled off to obtain 4(3-fluoro-4-trifluoromethoxyphenyl)cyclohexanecarboaldehyde 3.6 g (13.3 mmol). The yield was 57.6% from 4-(3-fluoromethoxy phenyl)cyclohexanone.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:3]1.Cl.[CH2:20]([S:22][C:23]1[C:31](O[C@@H]2CC[C@H](N)CC2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2)[CH3:21].C(SC1C(O)=CC=C2C=1C=NN2)C>>[CH2:20]([S:22][C:23]1[C:31]([O:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:3]2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2)[CH3:21]
Reactant: CCSc1c(O[C@H]2CC[C@@H](N)CC2)ccc2[nH]ncc12
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H](O)C1
Agent: CCSc1c(O)ccc2[nH]ncc12
Agent: Cl
Product: CCSc1c(O[C@@H]2CCC[C@H](N3C(=O)c4ccccc4C3=O)C2)ccc2[nH]ncc12

Procedure:
The title compound was synthesized by carrying out reaction according to the method described in Example 610, except for using the trans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained in Example 385, (b) and the 4-(ethylthio)-1H-indazol-5-ol obtained in Example 628, as starting materials.
Reaction SMILES: [CH2:1]([N:4]([CH:10]([CH3:13])[CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].O.[CH2:15]([NH:22][CH2:23]C(O)=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([N:22]1[CH2:23][CH2:3][CH:2]2[CH:11]1[CH:10]([CH3:13])[N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCN(C(=O)OCC)C(C)C=O
Reactant: O=C(O)CNCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC2CCN(Cc3ccccc3)C2C1C

Procedure:
37 g (0.2 mol) of ethyl N-allyl-N-(1-oxo-2-propyl)-carbamate are heated under reflux overnight in a water separator with 33 g (0.2 mol) of N-benzylglycine in 500 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [CH2:1]([N:6]1[CH2:10][C:9]2([CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)[O:8][C:7]1=[O:20])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[CH3:21][C:12]1([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:14][CH2:15][C:9]2([O:8][C:7](=[O:20])[N:6]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:10]2)[CH2:11]1
Reactant: COC(=O)C1CCCC2(C1)CN(CC(C)(C)C)C(=O)O2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCCC2(CN(CC(C)(C)C)C(=O)O2)C1
Temperature: -78 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a 78° C. solution of methyl 3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-carboxylate (15.0 g, 52.9 mmol) in THF (41.0 mL) under N2 was added sodium bis(trimethylsilyl)amide, 1 M in THF (238 mL, 238 mmol) over 1 h using an addition funnel. The reaction mixture was stirred at −78° C. for 3 h. Iodomethane (14.9 mL, 238 mmol) was added, and the reaction was stirred at −78° C. for an additional 2 h. The reaction was quenched at −78° C. with water (5 mL) and diluted with brine (200 mL). The product was extracted into EtOAc (3×200 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to a light yellow solid. The solid was suspended in Et2O (75 mL) and collected in a frit. The collected solids were washed with cold Et2O (4×10 mL) and dried to afford the title compound (13.4 g, 81% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 3.40 (d, J=8.78 Hz, 1H), 3.29 (d, J=8.78 Hz, 1H), 3.06 (d, J=14.05 Hz, 1H), 2.92 (d, J=14.05 Hz, 1H), 2.16 (d, J=14.05 Hz, 1H), 1.77-1.93 (m, 4H), 1.43-1.69 (m, 3H), 1.35 (s, 3H), 0.96 (s, 9H). MS (m/z) 298.1 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:23])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH2:20])=[O:14])=[CH:11][C:5]=2[O:4][C:3]1([F:22])[F:21].NC1C=CC2OC(F)(F)C(F)(F)OC=2C=1.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][N:46]=2)[C:41]([CH:48]=O)=[CH:40]1>>[F:23][C:2]1([F:1])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][CH2:48][C:41]3[C:42]4[C:47](=[N:46][CH:45]=[CH:44][CH:43]=4)[NH:39][CH:40]=3)=[O:14])=[CH:11][C:5]=2[O:4][C:3]1([F:22])[F:21]
Reactant: Nc1ccsc1C(=O)Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Product: O=C(Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2)c1sccc1NCc1c[nH]c2ncccc12

Procedure:
EXAMPLE 10 was prepared according to the procedure described in EXAMPLE 5 using N-(2,2,3,3-tetrafluorobenzodioxan-6-yl) 3-aminothiophene-2-carboxamide (prepared as described in example 1 part 1, using 6-amino-2,2,3,3-tetrafluorobenzodioxan instead of 4-trifluoromethoxyaniline) and 7-azaindole-3-carboxaldehyde (EXAMPLE 8, part 1) instead of 2-(N-methylcarbamoyl)pyridine-4-carboxaldehyde. MS (ES+): 479 [MH+]
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH:19]2[CH2:22][N:21]([C:23](=[O:25])[CH3:24])[CH2:20]2)[CH:5]=[CH:4][N:3]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32]([OH:36])([C:34]#[CH:35])[CH3:33])[CH:28]=1.C(N(CC)CC)C>CS(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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:35]#[C:34][C:32]([OH:36])([C:29]4[CH:28]=[C:27]([CH3:26])[O:31][N:30]=4)[CH3:33])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH:19]2[CH2:22][N:21]([C:23](=[O:25])[CH3:24])[CH2:20]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: CC(=O)N1CC(Oc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)N1CC(Oc2nc3ccc(C#CC(C)(O)c4cc(C)on4)cc3n2-c2ccnc(N)n2)C1
Temperature: 70 °C
Reaction time: 5 h
Yield: 21.8 %

Procedure:
A mixture of 1-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-one (130 mg, 0.29 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (200 mg, 1.32 mmol), bis(triphenylphosphine)palladium(II) dichloride (250 mg, 0.36 mmol) and triethylamine (1 mL) in DMSO (2 mL) was stirred under nitrogen for 5 h at 70° C. The reaction mixture was cooled to room temperature then filtered through a frit filter. The filtrate was purified by preparative HPLC to give 30 mg (21%) of 1-(3-[[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-one as a white solid: 1H NMR (400 MHz, DMSO) delta 8.41 (d, J=5.6 Hz, 1H), 8.19 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.11-7.07 (m, 3H), 6.45 (s, 1H), 6.38 (s, 1H), 5.57 (t, J=3.6 Hz, 1H), 4.61 (t, J=8.0 Hz, 1H), 4.37-4.29 (m, 2H), 4.03 (t, J=5.2 Hz, 1H), 2.41 (s, 3H), 1.81 (d, J=4.4 Hz, 6H); LC-MS: m/z=+474 (M+H)+.