Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([I:12])[C:9]([CH3:13])=[CH:8][C:3]=1[NH:4][CH:5]([CH3:7])[CH3:6].C(N(C(C)C)C(C)C)C.[Cl-].[C:24]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:25][CH2:26][C:27]([O-])=[O:28]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:11]=[C:10]([I:12])[C:9]([CH3:13])=[CH:8][C:3]=1[N:4]([C:27](=[O:28])[CH2:26][CH2:25][C:24]([O:31][CH2:32][CH3:33])=[O:30])[CH:5]([CH3:7])[CH3:6]
Reactant: CCOC(=O)CCC(=O)[O-]
Reactant: Cc1cc(NC(C)C)c(C)cc1I
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)N(c1cc(C)c(I)cc1C)C(C)C
Temperature: 25 °C

Procedure:
2.0 g (6.9 mmol) of 2,5-dimethyl-4-iodo-N-isopropyl-aniline and 2.4 ml of (13.8 mmol) of N-ethyl-diisopropylamine are dissolved in 30 ml of tetrahydrofuran and, after the addition of 1.5 ml (10.5 mmol) of ethyl succinate chloride, refluxed for 2 hours. After cooling to ambient temperature the mixture is diluted with ethyl acetate and washed successively with 1 molar hydrochloric acid and 1 molar sodium hydroxide solution. The organic phase is dried over sodium sulphate and evaporated down.
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.[CH:16]([N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=[CH2:17].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:28]=[C:19]1[C:20]2[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:23])[N:18]1/[CH:16]=[CH:17]/[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)c1cc(OC(C)C)ncc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OC(C)C)ncc1/C=C/N1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Yield: 34.3 %

Procedure:
To a solution of methyl 5-bromo-2-(propan-2-yloxy)pyridine-4-carboxylate (112a, 3.40 g, 12.4 mmol) and N-vinylphthalimide (2.58 g, 14.9 mmol) in toluene (124 mL) was added K2CO3 (5.19 g, 37.2 mmol) followed by Pd(P(tBu)3)2 (0.400 g, 0.775 mmol). The reaction mixture was degassed and heated in a sealed tube at 110° C. for 18 hours. The reaction mixture was cooled to room temperature and filtered through CELITE®. H2O (100 mL) was added, the organic layer was separated and concentrated under vacuum, and the residue was purified by column chromatography (0-80%, ethyl acetate/heptanes) to give methyl 5-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]-2-(propan-2-yloxy)pyridine-4-carboxylate (112b, 1.56 g, 34%) as yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[CH3:16][C:3]1([CH2:2][N:18]2[CH2:19][CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]2)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCc3ccccc3C1)O2

Procedure:
A suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.4 g), 1,2,3,4-tetrahydroisoquinoline (1.3 g), and potassium carbonate (1.4 g) in N,N-dimethylacetamide (10 mL) was refluxed under nitrogen gas for 15 hours. This reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to provide 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1,2,3,4-tetrahydroisoquinolin-2-yl)methyl]-5-benzofuranamine. This product was dissolved in ethanol, followed by addition of 1 equivalent of oxalic acid solution in ethanol. This mixture was heated and the resulting solution was concentrated under reduced pressure. The crystals that separated out were collected to provide 1.5 g of the title compound. Yield 68%.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([O:8][C:3]2[C:2]([C:21]3[CH:20]=[CH:19][C:18]([C:32]4[CH:37]=[N:36][C:35]([NH2:38])=[N:34][CH:33]=4)=[C:17]([F:16])[CH:22]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:10][CH2:11]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: N[C@H]1CC[C@H](Oc2ncccc2Br)CC1
Product: Nc1ncc(-c2ccc(-c3cccnc3O[C@H]3CC[C@H](N)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using trans-4-((3-bromopyridin-2-yl)oxy)cyclohexanamine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H22FN5O, 379.18; m/z found, 380.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=1.1, 2H), 8.15 (dd, J=4.9, 1.7, 1H), 7.81 (dd, J=7.4, 1.7, 1H), 7.53 (m, 3H), 7.05 (dd, J=7.4, 5.0, 1H), 6.87 (s, 2H), 5.02 (m, 1H), 2.63 (m, 1H), 2.05 (m, 2H), 1.77 (m, 2H), 1.39 (m, 2H), 1.18 (m, 4H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[NH:23][C:16]3[N:17]=[C:18]([NH2:22])[NH:19][C:20](=[O:21])[C:15]=3[CH:14]=2)=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+].CO.C(Cl)(Cl)Cl>CO>[NH2:22][C:18]1[NH:19][C:20](=[O:21])[C:15]2[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)[NH:23][C:16]=2[N:17]=1
Reactant: COC(=O)c1ccc(CCCc2cc3c(=O)[nH]c(N)nc3[nH]2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc2[nH]c(CCCc3ccc(C(=O)O)s3)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To a solution of 8 (300 mg, 0.9 mmol) in MeOH (10 mL) was added 1 N NaOH (10 mL) and the mixture was stirred under N2 at room temperature for 16 h. TLC showed the disappearance of the starting material (Rf=0.56) and one major spot at the origin (MeOH/CHCl3 1:5). The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in water (10 mL), the resulting solution was cooled in an ice bath, and the pH was adjusted to 3-4 with dropwise addition of 1 N HCl. The resulting suspension was frozen in a dry ice-acetone bath, thawed to 4-5° C. in the refrigerator, and filtered. The residue was washed with a small amount of cold water and dried in vacuum using P2O5 to afford 254 mg of 9 as white powder. 1H NMR (DMSO-d6): δ 1.89-1.96 (m, 2H), 2.49-2.55 (t, J=7.2 Hz, 2H), 2.80-2.84 (t, J=7.2 Hz, 2H), 5.88 (s, 1H), 5.98 (s, 2H), 6.92-6.93 (d, J=3.6 Hz, 1H), 7.55-7.56 (d, J=3.6 Hz, 1H), 10.14 (s, 1H), 10.83 (s, 1H) 12.86 (br, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:8])=[C:5]([F:7])[F:6].[S-:9][C:10]#[N:11].[NH4+]>>[F:8][C:4](=[C:5]([F:7])[F:6])[CH2:3][CH2:2][S:9][C:10]#[N:11]
Reactant: FC(F)=C(F)CCBr
Reactant: N#C[S-]
Agent: [NH4+]
Product: N#CSCCC(F)=C(F)F

Procedure:
When, for example, 4-bromo-1,1,2-trifluoro-1-butene and ammonium thiocyanate are used, 3,4,4-trifluoro-3-butenyl thiocyanate is obtained which is then reacted with H2S to give 3,4,4-trifluoro-3-butenyl dithiocarbamate. Further reaction of 3,4,4-trifluoro-3-butenyl dithiocarbamate with chloroacetaldehyde then provides 2-[(3,4,4-trifluoro-3-butenyl)sulphanyl]-1,3-thiazole. This reaction sequence may be schematically represented as follows:
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][C@@H:42]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[C@@H:41]([C:52]([OH:54])=[O:53])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[CH3:1][O:53][C:52]([C@@H:41]1[C@H:42]([C:45]2[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=2)[CH2:43][CH2:44][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:38])[CH2:40]1)=[O:54]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@@H](C(=O)O)C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.9 %

Procedure:
To a solution of triphenylphosphine (3.82 g, 14.6 mmol) in 70 ml tetrahydrofuran was added diethyl azodicarboxylate (2.53 g, 14.6 mmol) at 0° C. After 30′ methanol (4.55 ml, 112.0 mmol) and a solution of (+)-(3R,4R)-4-(4-fluoro-phenyl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (3.62 g, 11.2 mmol, 93.6% ee) in 30 ml tetrahydrofuran were added subsequently at 0-5° C. The reaction mixture was stirred for 20 h at room temperature. Quenching with water was followed by extraction with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and purified by flash chromatography (n-heptane/ethyl acetate) to give the title compound (3.55 g, 94%) as a colorless oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][CH:13]([OH:17])[CH2:14][CH:15]=[CH2:16].Cl>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:17][CH:13]([CH2:14][CH:15]=[CH2:16])[CH3:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: C=CCC(C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 3.5 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, p-toluenesulfonyl chloride (16.92 g, 88.75 mmol) was added to a cold (2° C.), stirring solution of 4-penten-2-ol (7.28 g, 84.52 mmol) in pyridine (60 mL). The solution was stirred at 2-5° C. for 2 h and allowed to warm to ambient temperature over several hours. The mixture, containing white solids, was poured into cold 3M HCl solution (250 mL) and extracted with CHCl3 (4×75 mL). The combined CHCl3 extracts were washed with 3M HCl solution (4×100 mL), saturated NaCl solution (2×50 mL), dried (Na2SO4), filtered, concentrated on a rotary evaporator, and further dried under high vacuum to afford 17.38 g (85.6%) of a light-amber oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 120 °C
Yield: 37.7 %

Procedure:
A stirred mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (150 mg, 0.384 mmol) from Step 3 of this Example, (1R,2R)-(−)-2-aminocyclohexanol (88 mg, 0.768 mmol), and DIEA (99 mg, 0.768 mmol) in anhydrous DMA (3 mL) in a sealed vial was heated in a Biotage microwave synthesizer at 120° C. for 30 min. After the reaction mixture was cooled to rt, it was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol (64 mg, 38%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.38 (d, J=1.7 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.39 (s, 1H), 7.10-7.16 (m, 2H), 5.48 (s, 2H), 4.69 (d, J=4.2 Hz, 1H), 3.30-3.40 (m, 2H), 1.83-1.97 (m, 2H), 1.57-1.67 (m, 2H), 1.15-1.30 (m, 4H). LCMS (ESI) m/z 442 and 444 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[F:13][C:14]1[CH:15]=[C:16]([CH2:21][OH:22])[CH:17]=[C:18]([F:20])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:21][O:22][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: OCc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(OCc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A solution of 5-fluoro-2-nitrobenzonitrile (60 g, 354 mmol), (3,5-difluorophenyl)methanol (52.14 mL, 460 mmol) and cesium carbonate (155 g, 460 mmol) in dry DMF (720 mL) was stirred at 70° C. for 6 hours. The reaction mixture was cooled at room temperature and poured into water (7 L) under stirring. The so obtained precipitated was filtered, washed with water and dried under vacuum at 50° C., affording 95 g (yield 92%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][CH2:21]Cl.O>CN(C)C=O>[CH3:19][O:20][CH2:21][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1]
Reactant: COCCl
Reactant: Oc1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-trifluoromethoxyphenol (10.00 g) was dissolved in N,N-dimethylformamide (50 mL), and potassium carbonate (15.52 g) and chloromethyl methyl ether (4.70 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and then the mixture was extracted with n-hexane. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (12.21 g) as a colorless oily substance.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[NH2:22]>C(Cl)(Cl)Cl>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[NH:22][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Nc1ccc2ccccc2c1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(O)cc1Nc1ccc2ccccc2c1
Temperature: 180 °C
Reaction time: 8 h

Procedure:
3 g of 3-fluoro-4-nitrophenol and 8.2 g of 2-naphthylamine were mixed and stirred for 8 hours at 180° C. The raw mixture was taken up in chloroform and washed with 2N aqueous hydrochloric acid. The organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].CCN(CC)CC.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:35](=[O:36])[N:34]([CH3:38])[CH3:33]
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 399.9 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added Et3N (0.141 mL, 1 mmol) and N,N-dimethylcarbamoyl chloride (0.08 g, 0.075 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.15 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([M−H]−); IR (thin film) 3350, 1705, 1114, 808 cm−1.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH2:25]([CH:27]([CH2:30][CH3:31])[CH:28]=O)[CH3:26]>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:28][CH:27]([CH2:30][CH3:31])[CH2:25][CH3:26])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CCC(C=O)CC
Solvent: CC(=O)N(C)C
Product: CCC(C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21)CC
Temperature: 25 °C
Yield: 68.3 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 2-ethylbutanal (0.5 g, 5.2 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 130° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.082 g, 68%).
Reaction SMILES: C([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=O)C>Cl>[NH2:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[CH:7][C:6]=1[C:15]([F:18])([F:16])[F:17]
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Agent: Cl
Product: Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Yield: 49.4 %

Procedure:
A mixture of 2-acetamido-5-fluoro-3-nitrobenzotrifluoride (1.50 g, 5.64 mmol) in concentrated HCl (10 mL) was refluxed overnight and it was extracted by ethyl acetate (2×10 mL). The extract was dried over Mg2SO4, and evaporated to give 624 mg of 2-amino-5-fluoro-3-nitrobenzotrifluoride (50%). 1H NMR (CDCl3): δ6.547 (s, 2H), 7.570 (dd, 1H, J1 =2.7 Hz, J2 =5.7 Hz), 8.114 (dd, 1H, J1 =2.7 Hz, J2 =5.7 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:16]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[C:14]2[C:23](=[O:37])[N:24](CC3C=CC(OC)=CC=3OC)[CH2:25][C:13]=2[C:12]=1[F:38].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:16]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[C:14]2[C:23](=[O:37])[NH:24][CH2:25][C:13]=2[C:12]=1[F:38]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC(F)(F)[C@@H]4N)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)c(F)c3c2C(=O)NC3)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.7 %

Procedure:
To a solution of 6-(cis-2-amino-3,3-difluorocyclohexylamino)-2-(2,4-dimethoxybenzyl)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (21 mg, 0.040 mmol) in DCM (300 μL) was added TFA (500 μL, 6.49 mmol). The reaction mixture was stirred at ambient temperature for 12 h then an additional 3 h at 50° C. The mixture was subsequently concentrated to a dark oil and diluted with DMF (1 mL) which was purified via preparative HPLC and lyophilized to give a TFA salt of the title compound as a fluffy white solid (3.6 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.89 (s, 1H), 8.43 (s, 3H), 8.16 (s, 1H), 6.89 (br s, 1H), 6.54 (br s, 1H), 4.65-4.52 (m, 1H), 4.49-4.32 (m, 2H), 4.17 (br s, 1H), 3.89 (s, 3H), 2.37-2.03 (m, 2H), 1.84 (br s, 3H), 1.63 (br s, 1H). [M+H] calc'd for C17H19F3N6O, 381. found, 381.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]#[N:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>CO.C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH:1]1[C:13]2[CH:12]([CH2:14][C:15]#[N:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CC=C1c2ccccc2-c2ccccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CCC1c2ccccc2-c2ccccc21
Reaction time: 6 h

Procedure:
610 mg (3 mmol, 1 eq) of fluoren-9-ylidene-acetonitrile in solution in 40 mL of methanol and 10 mL of ethyl acetate, then 225 mg of palladium hydroxide over coal were introduced into a 250 mL flask under a nitrogen atmosphere. The reaction medium was purged then placed under a hydrogen atmosphere (skin flask) and stirred for 6 hours while stirring. The catalyst was removed by filtration over Clarcel. The solvent was evaporated and the expected product was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C@H:12]([C:21]([OH:23])=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.[Cl-].[NH4+]>CO.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C@H:12]([C:21]([OH:23])=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](COc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](COc1ccccc1N)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
A mixture of 8.98 g (0.0275M) of O-(o-nitrophenyl)-N-t-butoxycarbonyl-D-serine, 2.95 g (0.0551M) of ammonium chloride (NH4Cl) and 25 g (0.3856M) of zinc dust in 200 mL of methanol was stirred at room temperature for 18 hours. The solvent was evaporated and the residue dissolved in 200 mL of a 50/50 mixture of ethyl acetate and chloroform. The mixture was filtered and the filtrate evaporated to yield 8.15 g (100%) of product as an oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[C:7]([CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:6]=[CH:5]4)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc2nc(CN3CCCC3)ccc2c1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4nc(CN5CCCC5)ccc4c3)nc2)cc1

Procedure:
Prepared according to general working method I from 6-iodo-2-pyrrolidin-1-ylmethyl-quinoline (151 mg, 0.45 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (80 mg, 0.37 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH:43]([C:45]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[OH:44]>>[CH2:53]([O:52][C:46]1[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:45]=1[CH:43]([OH:44])[CH2:42][NH:41][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCC(O)c1cc(Cl)ccc1OCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCC(O)c1cc(Cl)ccc1OCc1ccccc1
Yield: 64.2 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (75 mg, 0.13 mmol) and 2-amino-1-[2-(benzyloxy)-5-chlorophenyl]-1-ethanol (45 mg, 0.16 mmol) according to Method C to give the title compound (66 mg) as a diasteromeric mixture. 1H-NMR (400 MHz, CD3OD) d 4.77 (s, 1H), 4.75 (s, 1H), 4.55 (m, 1H), 4.22 (m, 1H), 1.33-1.32 (9H); HRMS m/z 789.2713 (calc. of monoisotopic mass for C41H44ClN3O11 gives 789.2664).