Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]#[N:17])=[CH:11][CH:12]=2)[N:7]([CH3:18])[CH:6]=1)C=C.Cl>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(O)C>[C:16]([C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:15])[C:5]([OH:4])=[CH:6][N:7]2[CH3:18])=[CH:12][CH:11]=1)#[N:17]
Reactant: C=CCOc1cn(C)c2cc(C#N)ccc2c1=O
Agent: [Rh]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: Cn1cc(O)c(=O)c2ccc(C#N)cc21

Procedure:
A mixture of the crude 3-allyloxy-7-cyano-1-methyl-4-quinolone (1.2 g), tris(triphenylphosphine)rhodium chloride (0.1 g) and ethanol (200 ml) was heated under reflux for 2 days. Hydrochloric acid (1M, 10 ml) was added, the mixture heated under reflux for 2 hours and then the solvent was evaporated under reduced pressure at 50°. The residue was extracted with aqueous sodium hydroxide (1M, 50 ml) and the extract neutralised with hydrochloric acid (12M, 4 ml). The resultant solid was collected by filtration and washed with water (10 ml) t give the novel compound 7-cyano-3-hydroxy-1-methyl-4-quinolone, m.p. 305°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([O:16]CC)=O)=[C:5]2[OH:19].[C:20]([NH:29][NH2:30])(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([NH:30][NH:29][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:16])=[C:5]2[OH:19]
Reactant: CCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2cc(Br)ccc2n(C)c1=O
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2cc(Br)ccc2n(C)c1=O

Procedure:
Reagents: Comp 35 (0.46 mmols, 0.15 g); octanoyl hydrazine (0.5 mmols, 0.08 g). Yield: 0.13 g (64%), white solid, m.p.=185° C.-186° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:22])[C@H:12]([CH3:21])[NH:13]C(OC(C)(C)C)=O)[CH3:2].[ClH:24]>C(OCC)(=O)C>[ClH:24].[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:22])[C@H:12]([CH3:21])[NH2:13])[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H]1CCCN1C(=O)[C@H](C)N
Reaction time: 0.75 h

Procedure:
To the product of Step C above (1.125 g) in 3 ml of ethyl acetate at 0° C. was added 6 ml of 5.8M hydrogenchloride in ethyl acetate, an the mixture was kept at 0° C. for 45 minutes. It was then concentrated to dryness; ether (20 ml) was added, and the crystalline hydrochloride salt was collected by filtration and washed with ether: 715 mg (80%) m.p. 175°-8° C.; TLC Rf =0.47 silica gel 4:1:1-n-butanol:water:acetic acid.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:21])([F:20])[CH2:18]O>>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:18][C:17]([F:21])([F:20])[F:16])(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCC(F)(F)F
Product: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reaction time: 0.5 h
Yield: 73 %

Procedure:
In a 100-ml flask equipped with a stirrer, a thermometer, a nitrogen introducing pipe and a condenser, 50 ml (0.297 mol) of trifluoromethanesulfonic anhydride and 25 ml (0.342 mole) of 2,2,2-trifluoroethanol were placed at room temperature and stirred for 30 minutes in a nitrogen atmosphose, followed by reflux for 3 hours. After distillation, 50.3 g of 2,2,2-trifluoroethyl trifluoromethanesulfonate was obtained in yield of 73%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:35][C:34](=O)[NH:33][N:32]=2)=[CH:27][CH:26]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[C:34]1[CH:35]=[C:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)[NH:32][N:33]=1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Product: COc1ccc(-c2cc(-c3ncnc4cc(OCC5CCN(C)CC5)c(OC)cc34)n[nH]2)cc1
Yield: 0.1 %

Procedure:
Using a procedure analogous to that described in Example 15, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (140 mg, 0.435 mol), (prepared as described for the starting material in Example 15), was reacted with 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (100 mg, 0.52 mol), (prepared as described for the starting material in Example 10), to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(5-(4-methoxyphenyl)pyrazol-3-yl)quinazoline (174 mg, 84%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][C:10](=[O:19])[NH:9]2)[CH:5]=[CH:4][CH:3]=1.[Br:20]C1C=CN=C(C=O)C=1>>[Br:20][C:4]1[CH:3]=[CH:2][N:7]=[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][C:10](=[O:19])[NH:9]2)[CH:5]=1
Reactant: O=Cc1cc(Br)ccn1
Reactant: O=C1N[C@H](c2cccc(Br)n2)[C@@H](c2ccccc2)O1
Product: O=C1N[C@H](c2cc(Br)ccn2)[C@@H](c2ccccc2)O1

Procedure:
Prepared according to the same procedure as (±)-(4R,5R)-4-(6-bromopyridin-2-yl)-5-phenyloxazolidin-2-one, starting with 4-bromopicolinaldehyde. 1H-NMR (CDCl3, 500 MHz) δ 8.49 (d, J=5.5, 1H), 7.63 (d, J=1.8, 1H), 7.50 (dd, J=5.2, 1.8, 1H), 7.36-7.48 (m, 5H), 6.77 (bs, 1H), 5.60 (d, J=5.5, 1H), 4.93 (d, J=5.5, 1H). 13C-NMR (CDCl3, 126 MHz) δ 160.2, 159.1, 151.0, 138.3, 134.3, 129.12, 129.09, 127.0, 125.7, 124.3, 83.7, 64.6. Mass spec.: 319.1 (MH)+.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>CO>[CH:27]1([NH:30][CH2:2][C:3]2([OH:1])[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:7][CH2:8]2)[CH2:29][CH2:28]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: NC1CC1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CNC4CC4)CC3)c(F)c2)C(=O)O1
Yield: 73 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with cyclopropylamine (2.06 mmol) in methanol (10 ml) at a temperature 25° C. for 14 hours and by purifying the compound by silica gel column chromatography in 73% yield.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12](OS(C(F)(F)F)(=O)=O)[C:13]3[O:22][C:21]4[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][C:16]=4[C:14]=3[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:38]([Sn](CCCC)(CCCC)C=C)[CH2:39]CC.[Cl-].[Li+]>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:38]=[CH2:39])[C:13]3[O:22][C:21]4[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:17][C:16]=4[C:14]=3[CH:15]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(OS(=O)(=O)C(F)(F)F)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1cc(S(=O)(=O)c2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 100 °C
Yield: 60.7 %

Procedure:
A mixture of tert-butyl 8-(phenylsulfonyl)-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (200 mg, 0.45 mmol), tributyl(vinyl)stannane (0.11 mL, 0.48 mmol), lithium chloride (45 mg, 1.34 mmol) and palladium tetrakis(triphenylphosphine) (8 mg, 0.01 mmol) was suspended in anhydrous 1,4-dioxane (5 mL). The flask was purged with argon, sealed, and heated to 100° C. for 3 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 9:1 hexanes/ethyl acetate) to give tert-butyl 8-(phenylsulfonyl)-6-vinyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (120 mg, 77%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.00-7.90 (m, 3H), 7.86 (s, 1H), 7.61-7.45 (m, 3H), 7.00-6.84 (m, 1H), 6.23 (d, J=17.4 Hz, 1H), 5.60 (d, J=17.4 Hz, 1H), 4.57 (s, 2H), 3.84 (t, J=5.7 Hz, 2H), 2.88 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:7]=1.C1C(O)=CC=C(O)C=1.OP(O)(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:7]=1
Reactant: CC(C)(O)c1cc(Br)ccc1F
Agent: O=P(O)(O)O
Agent: Oc1ccc(O)cc1
Solvent: ClCCl
Product: C=C(C)c1cc(Br)ccc1F
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2-(5-bromo-2-fluoro-phenyl)-propan-2-ol (119.7 g, 498 mmol) in CH2Cl2 (50 ml) was added hydrochinone (2.74 g, 24.9 mmol) and 250 ml 85% H3PO4. The resulting reaction mixture was stirred for 3.5 h at 50° C. The mixture was poured onto ice-water and extracted with CH2Cl2. The organic phases were washed with 2N aqueous NaOH and water, dried over MgSO4, filtered and concentrated. The crude product was dissolved in hexane and filtered through a plough of silica gel to obtain after concentration at 600 mbar the title compound as a colorless oil: TLC (hexane): Rf=0.52; UPLC RtH5=1.416 min; 1H NMR (360 MHz, CDCl3): δ 7.43 (dd, 1H), 7.37 (m, 1H), 6.94 (dd, 1H), 5.27 (d, 2H), 2.13 (s, 3H).
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14](Cl)[CH:13]=[C:12]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].[CH3:25][C@H:26]1[O:31][C@@H:30]([CH3:32])[CH2:29][NH:28][CH2:27]1.C(Cl)Cl>O1CCOCC1.O.O>[N:1]1([C:10]2[N:15]=[C:14]([N:28]3[CH2:27][C@@H:26]([CH3:25])[O:31][C@@H:30]([CH3:32])[CH2:29]3)[CH:13]=[C:12]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Clc1cc(N2CCOCC2)nc(-n2cnc3ccccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2cc(N3CCOCC3)nc(-n3cnc4ccccc43)n2)C[C@H](C)O1
Temperature: 80 °C
Reaction time: 12 h
Yield: 86.2 %

Procedure:
To the obtained 2-(benzimidazol-1-yl)-4-chloro-6-morpholinopyrimidine (318 mg, 1.00 mmol) dissolved in dioxane—water solution (4:1), sodium hydroxide (100 mg, 4.3 mmol) and cis-2,6-dimethylmorpholine (126 mg, 1.20 mmol) were added and stirred at 80° C. for 12 hours. The reaction mixture was condensed under reduced pressure and the obtained residue was mixed with methylene chloride and water and shaken. Organic layer was separated from the mixture and washed with water and dried over anhydrous magnesium sulfate. The solvent was removed out under reduced pressure and the residue was purified by silica gel column chromatography to obtain 340 mg of the titled compound (yield: 86%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH:24]([CH3:26])[CH3:25])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[N:41][CH:42]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.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].C(Cl)Cl>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:37]3[CH:42]=[N:41][C:40]([N:43]4[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]4)=[CH:39][CH:38]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH:24]([CH3:26])[CH3:25])=[O:15])[C:5]=2[CH:6]=[N:7]1)([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Reactant: Cc1cc(C(C)C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(C)C)c(CNC(=O)c2cc(-c3ccc(N4CCNCC4)nc3)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-1-(1-methylethyl)-N-{[6-methyl-4-(1-methylethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1H-indazole-4-carboxamide (90 mg, 0.2 mmol), {1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (88 mg, 0.3 mmol) in dioxane/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 adduct (4.95 mg, 0.006 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (50.9 mg, 0.61 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 100° C. for 20 min. Upon cooling down, any solids that crashed out were filtered. DCM/MeOH (1:1) was added, the contents pre-absorbed on silica gel, and purified by SiO2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). The collected product was then further purified by reverse-phase HPLC (15% to 80% CH3CN in water with 0.1% TFA), which afforded the product as a TFA salt. CH3CN was evaporated and a saturated solution of sodium bicarbonate was added to the water layer followed by DCM/isopropanol (70:30). The organic layer was separated, and the aqueous layer was further extracted with DCM/isopropanol (70:30). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. DMF was added along with some water, and after sitting overnight, the solids that precipitated were filtered. EtOAc was added along with some hexanes, the contents sonicated, and the solids that precipitated were filtered and dried to afford the title compound as an off-white solid (29.5 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br. s., 1H) 8.59-8.68 (m, 2H) 8.35 (s, 1H) 8.00-8.12 (m, 2H) 7.83 (s, 1H) 6.92 (d, J=8.84 Hz, 1H) 6.03 (s, 1H) 5.13 (quin, J=6.63 Hz, 1H) 4.47 (br. s., 1H) 4.46 (br. s., 1H) 3.42-3.56 (m, 4H) 3.20-3.27 (m, 1H) 2.76-2.85 (m, 4H) 2.16 (s, 3H) 1.50 (s, 3H) 1.49 (s, 3H) 1.11 (s, 3H) 1.09 (s, 3H). LC-MS (ES) m/z=528.1 [M+H]+
Reaction SMILES: [CH2:1]([N:8]([CH3:34])[C:9]([CH:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[C:12]([NH:14][C@@H:15]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:16](O)=[O:17])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C.[NH2:68][CH2:69][CH:70]1[CH2:75][CH2:74][CH:73]([C:76]#[N:77])[CH2:72][CH2:71]1>CN(C)C=O>[CH2:1]([N:8]([CH3:34])[C:9](=[O:10])[CH:11]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[C:12]([NH:14][C@H:15]([C:16](=[O:17])[NH:77][CH2:76][CH:73]1[CH2:74][CH2:75][CH:70]([C:69]#[N:68])[CH2:71][CH2:72]1)[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1CCC(CN)CC1
Reactant: CN(Cc1ccccc1)C(=O)C(Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)C(Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)NCC1CCC(C#N)CC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
To [2-(R,S)-(Benzyl-methyl-carbamoyl)-3-(4-cyano-phenyl)-propionylamino]-(S)-cyclohexyl-acetic acid (910 mg, 1.97 mmol) in dimethylformamide (150 ml) were added HATU (825 mg, 2.17 mmol) and collidine (263 mg, 2.17 mmol) at 0° C. After 30 minutes at 0° C. 4-aminomethyl-cyclohexanecarbonitrile (272 mg, 1.97 mmol) was added. The mixture was stirred for 1 hour, then allowed to warm to room temperature, and stand at room temperature for 72 hours. After evaporation the residue was stirred with Na2CO3 solution and the precipitate was sucked off to yield 1.18 g of the desired product which was used for further reactions without purification.
Reaction SMILES: [CH2:1]([CH2:16][C:17](=O)[CH3:18])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[C:20]([CH:22]([CH:17]([CH3:18])[CH2:16][CH2:1]/[CH:2]=[C:3](\[CH3:4])/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:9])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)C(C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
In 200 ml of benzene was dissolved 50 g of farnesylacetone, and 28 g of ethyl cyanoacetate, 5 g of ammonium acetate and 5 g of acetic acid were added to the solution. The mixture was refluxed for 8 hours while removing the water formed by the reaction. The liquid reaction mixture was washed with water and dried and a solution of 4.3 g of sodium borohydride in 50 ml of ethanol was added dropwise to the reaction mixture under agitation at 10° to 20° C. The resulting mixture was stirred for 1 hour. To the liquid reaction mixture was added 50 ml of 10% acetic acid, and the mixture was washed with water and dried. The solvent was removed by distillation and the residue was purified by column chromatography using silica gel to obtain 50.5 g of the intended compound in the form of an oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][OH:37].[N+:39]([C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)([O-:41])=[O:40]>>[CH3:32][N:33]([CH2:34][CH2:35][CH2:36][O:37][C:45]1[CH:46]=[CH:47][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=1)[CH3:38]
Reactant: CN(C)CCCO
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
A stirred solution of diethyl azodicarboxylate (4.6 ml, 0.029 mole) and triphenylphosphine (7.60 g, 0.029 mole) in dry TBF (100 ml) was cooled to 0° C. 3-(Dimethylamino)propanol (3.43 ml, 0.029 mole) was added, followed by 4-nitrophenol (4.0 g, 0.029 mole) and the reaction mixture was stirred for 18 h at room temperature. The solvent was removed in vacuo, and the residue partitioned between 5N HCl and ethyl acetate. The aqueous layer was basified with 10% NaOH solution and extracted into ethyl acetate, dried (MgSO4) and evaporated in vacuo to leave the title compound as a yellow oil (3.2 g, 50%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30]([O:32]C)=[O:31])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH3:26])[CH2:17][CH:16]([N:27]([CH3:29])[CH3:28])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30]([OH:32])=[O:31])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH3:26])[CH2:17][CH:16]([N:27]([CH3:28])[CH3:29])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(N(C)C)CN(C)c1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CC(N(C)C)Cn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
To a solution of methyl 14-cyclohexyl-7-(dimethylamino)-5-methyl-5,6,7,8-tetrahydroindolo[1,2-e][1,5]benzodiazocine-11-carboxylate in MeOH (0.05 M), 40 eq 2N NaOH were added and the reaction stirred at 65° C. for 3 h. The reaction was acidified to pH 2 with HCl and the solvent was evaporated in vacuo. The crude was then purified by prep RP-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×150 mm. Mobile phase: acetonitrile/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a brown powder in 8 % yield (over four steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[C:5]2[C:16]([F:19])([F:18])[F:17].P(Br)(Br)([Br:22])=O>>[Br:22][C:7]1[C:6]([N+:13]([O-:15])=[O:14])=[C:5]([C:16]([F:19])([F:18])[F:17])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=[N+]([O-])c1c[n+]([O-])c2ccc(Cl)cc2c1C(F)(F)F
Product: O=[N+]([O-])c1c(Br)nc2ccc(Cl)cc2c1C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A mixture of 3 (4.71 g, 16.1 mmol) and POBr3 (9.23 g, 32.2 mmol) were heated to 100° C. After 2 h, the reaction was cooled to rt and partitioned between EtOAc and H2O, adding ice when necessary. The mixture was stirred overnight to break up the solid materials. Et2O (100 mL) was added and the organic phase was removed. The remaining aqueous phase was extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated to afford 5.5 g (96%) of the desired product which was used without further purification. An analytically pure sample was obtained by recrystallization (EtOH) to provide a fluffy off-white solid, mp 120° C. Rf 0.61 (10% Ethyl acetate-hexane). 1H NMR (CDCl3, 300 MHz) δ8.16 (d, J=9.1 Hz, 1H), 8.16 (m, 1H), 7.92 (dd, J=2.2, 9.1 Hz, 1H); 19F NMR (CDCl3, 300 MHz) δ−57.63; 13C NMR (CDCl3, 75 MHz) δ146.50, 137.35, 134.25, 131.88, 131.32, 124.45, 124.40, 122.44, 121.96, 118.76; IR (KBr) υmax 1606, 1588, 1552, 1492, 1426, 1382, 1361, 1308, 1283, 1219, 1180, 1169, 1157, 1134, 1097, 1023, 960, 846, 823, 792, 693, 661, 632 cm−1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.[F:16][C:17]([F:36])([F:35])[C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([CH2:33]Cl)[N:29]=2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>>[F:36][C:17]([F:16])([F:35])[C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([CH2:33][N:6]3[C:7]4[C:3](=[C:2]([Cl:1])[C:10]([C:11]#[N:12])=[CH:9][CH:8]=4)[CH:4]=[C:5]3[CH:13]([F:14])[F:15])[N:29]=2)[CH:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2noc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c1Cl

Procedure:
Synthesized as described in Example 39 from 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: MS (ESI) m/z 519 (M−1).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:8]=1>C(Cl)(Cl)Cl>[Br:1][C:6]1[S:5][C:4]([CH3:3])=[N:8][C:7]=1[C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1
Reactant: BrBr
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccc([N+](=O)[O-])cc2)c(Br)s1
Yield: 60 %

Procedure:
Bromine (6 mmol) was added dropwise to a solution of 2-methyl-4-(4-nitrophenyl)-1,3-thiazole (5 mmol) in chloroform (20 mL) and the solution refluxed for 4 h. The solvent was evaporated and the product purified by crystallization from ether to afford the title compound (60%). ESMS [M+H]+: 300.2