Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N+:41]([O-])([OH:43])=[O:42]>CC(O)=O>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([N+:41]([O-:43])=[O:42])[CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccccc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 0.75 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (example 143) (159.4 mg, 0.276 mmol) in HOAc (5 mL) was added HNO3 (1.5 mL). After 45 minutes, additional HNO3 (1.5 mL) was added. 45 minutes later, the reaction was quenched by pouring into ice water (30 mL). The mixture was extracted with EtOAc (75 mL), and the organic layer was washed with 1 N NaOH, saturated NaHCO3, and brine (25 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (8 to 40% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-nitro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.11 (25% EtOAc/hexanes). LCMS=623.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 8.34 (m, 1H), 8.10 (m, 1H), 7.85 (d, J=6.9 Hz, 1H), 7.61-7.71 (m, 4H), 7.40 (m, 1H), 7.11 (m, 1H), 5.66 (d, J=8.0 Hz), 5.28 (d, J=8.2 Hz), 4.89-4.94 (m, 1H), 3.74-4.09 (m, 5H), 0.61 (d, J=6.6 Hz), 0.47 (d, J=6.5 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:4]2[N:3]=1.[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[N:4]3[N:3]=[C:2]([NH:29][C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([NH2:30])[CH:24]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[CH:16][CH:17]=1
Reactant: Nc1cccc(N)c1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Cl)nn23)cc1
Product: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(N)c4)nn23)cc1

Procedure:
Starting from 6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine (compound B1) and m-phenylene-diamine, the title compound can be obtained analogously to one of the procedures as described for compound A1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH2:11])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:20](=[O:21])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:9][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1(c2ccc(Br)cn2)CC1
Solvent: CCN(CC)CC
Product: O=C(NC1(c2ccc(Br)cn2)CC1)OCc1ccccc1
Reaction time: 1 h

Procedure:
At 0° C., to the mixture of 1-(5-bromopyridin-2-yl)cyclopropanamine (1.07 g, 5.0 mmol), triethylamine (766 ul, 5.5 mmol) was added benzyl chloroformate (785 ul, 5.5 mmol). The resulting mixture was allowed to stir at it for 1 h. After work up, the crude product was purified by column chromatography on SiO2.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH:11]1([S:14]([CH2:17][C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[N:21]=[C:20]([C:31]3[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=3)[N:19]=2)(=[O:16])=[O:15])[CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH:11]1([S:14]([CH2:17][C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[N:21]=[C:20]([C:31]3[CH:32]=[CH:33][C:34]([NH:35][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:36][CH:37]=3)[N:19]=2)(=[O:15])=[O:16])[CH2:13][CH2:12]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CC2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
Phenyl chloroformate (0.315 mL, 2.50 mmol) was added dropwise to 4-[4-(cyclopropylsulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (972 mg, 2.50 mmol) and sodium bicarbonate (315 mg, 3.75 mmol) in dioxane (20 mL). The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the desired material (1.35 g).
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][OH:14])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[C:4]1(=[O:27])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH2:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][O:14][S:40]([CH3:39])(=[O:42])=[O:41])[C:1](=[O:32])[C:2]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:3]12
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCOS(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
To a mixture of 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-hydroxy-4-aza-octane (6.75 g 14.5 mM), dry dichloromethane (25 mL) and dry pyridine (10 mL), a solution of methanesulfonyl chloride (1.7 g) in dichloromethane (25 mL) is slowly added with stirring. The reaction mixture is kept at room temperature overnight, additional dichloromethane is added, and the reaction mixture is washed with 1N HCl (twice) and then washed with brine (twice). The resulting solution is dried (Na2SO4) and the solvent evaporated to yield an oil. Upon scratching this oil with ether/petroleum ether, the compound 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-methanesulfonyloxy-4-aza-octane is obtained as white crystals: 7.64 g (97%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1([S:15][CH2:16][CH2:17][F:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:9]1([S:15][CH:16]([Cl:1])[CH2:17][F:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: FCCSc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: FCC(Cl)Sc1ccccc1
Yield: 94.1 %

Procedure:
A solution of N-chlorosuccinimide (1.1 g; 8.25 mmol) and phenyl-(2-fluoroethyl)sulfide (1.28 g; 8.25 mmol) in 25 mL methylene chloride was stirred for 0.5 h at room temperature. Methylene chloride (25 mL) was added to the reaction mixture and washed with water (2×35 mL). The organic layer was dried and evaporated to yield 1.48 g phenyl-(1-chloro-2-fluoroethyl)sulfide as an oily material which was mixed with 6 (2.23 g; 9.9 mmol), triethylamine (1.0 g; 9.9 mmol) and dry acetonitrile (30 mL) and refluxed for 5 h. The solvent was removed in vacuo and the residue was dissolved in methylene chloride (75 mL) and washed with water (50 mL), 5% aqueous sodium bicarbonate (50 mL) and 5% hydrochloric acid (50 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent removed, leaving a crude product (2.78 g). The crude product was purified by flash chromatography using hexane/methylene chloride as the eluting solvent, mp 73°-74° C. (1.92 g; 62% yield). 1H NMR: δ 2.80-2.98(m, 1H), 3.2-3.45(m,4H), 4.6-4.8(m, 1H), 4.82-5.10(m, 1H), 5.45(m, 1H), 7.1-7.35(m,3H), 7.5-7.65(m,2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:14]([CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])CC1C=CC=CC=1>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][NH:14][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]
Reactant: COc1ccccc1OCCN(CCCc1c[nH]c2ccc(F)cc12)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1OCCNCCCc1c[nH]c2ccc(F)cc12
Reaction time: 20 h
Yield: 0.1 %

Procedure:
A mixture of [3-(5-fluoro1H-indol-3-yl)-propyl]-[2-(2-methoxy-phenoxy) ethyl]-benzylamine (0.94 g, 2.2 mol) and 10lo palladium on carbon (250 mg) in ethanol was hydrogenated for 20 hours. The catalyst was filtered off and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride) afforded 0.63 g (85%) of product as an off-white solid: mp 125-126° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1C(C2C=CC=CC=2[N+]([O-])=O)C(C(OC2CCCCC2)=O)=C(C)[NH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C(C(=O)OCc2ccccc2)C(c2ccccc2[N+](=O)[O-])C(C(=O)OC2CCCCC2)=C(C)N1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccccc1
Yield: 68 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-nitrobenzylideneacetoacetic acid cyclohexyl ester and 75 mmols of β-aminocrotonic acid benzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-cyclohexyloxycarbonyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid benzyl ester of melting point 134° C (from ethanol).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]3[CH2:22][CH2:21][CH2:20][N:19]3C(OC(C)(C)C)=O)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[C:7]([O:32][CH3:33])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.Cl>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3[CH2:22][CH2:21][CH2:20][NH:19]3)[CH:13]=2)=[O:10])=[C:7]([O:32][CH3:33])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(C)(C)C)ccc1C(=O)Nc1cccc(C2CCCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Product: COc1cc(C(C)(C)C)ccc1C(=O)Nc1cccc(C2CCCN2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.5 %

Procedure:
A solution of (±)-2-[3-(4-tert-butyl-2-methoxy-benzoylamino)-phenyl]-1-(tert-butyloxycarbonyl)-pyrrolidine (0.034 g) in methanol (3 mL) and 5M HCl (2 mL) was allowed to stir at room temperature for 18 h. Evaporation in vacuo gave the title compound as a colourless solid (0.029 g).
Reaction SMILES: [CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH3:28])[CH3:27])=[N:24][CH:25]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:27][N:26]([CH3:28])[C:23]1[N:24]=[CH:25][C:20]([N:16]2[CH2:15][CH2:14][CH:13]([N:2]([CH3:1])[C:3](=[O:12])[O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:18][CH2:17]2)=[CH:21][CH:22]=1
Reactant: CN(C)c1ccc(Br)cn1
Reactant: CN(C(=O)OCc1ccccc1)C1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)cn1
Temperature: 80 °C
Yield: 67 %

Procedure:
Benzyl methyl(piperidin-4-yl)carbamate (stage 3 AMN-52) (616 mg, 2.4875 mmol, 1.0 eq.), 5-bromo-2-dimethylaminopyridine (500 mg, 2.4875 mmol, 1.0 eq.) and KOBut (557 mg, 4.978 mmol, 2.0 eq.) were taken up in toluene (15 ml) and degassed with N2. BI NAP (77 mg, 0.124 mmol, 0.05 eq.) and Pd2(dba)3 (113 mg, 0.124 mmol, 0.05 eq.) were then added and the mixture was heated for 16 hours at 80° C. After monitoring by TLC, the reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, 2% MeOH in DCM). Yield: 67% (500 mg, 1.358 mmol)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[I-:16].[Na+]>CC(C)=O>[I:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: [I-]
Reactant: COC(=O)CCCCCCCCCCBr
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)CCCCCCCCCCI
Temperature: 22 °C
Reaction time: 19 h
Yield: 95 %

Procedure:
To a solution of commercially available methyl 11-bromoundecanoate (5.80 g, 20.8 mmol) dissolved in dry acetone (70 mL) was added sodium iodide (4.05 g, 27.0 mmol). The reaction mixture was stirred at room temperature (22° C.) for 19 h under an inert nitrogen atmosphere. Afterwards, the acetone was evaporated and the residue transferred into an extraction funnel with diethyl ether (100 mL) and water (40 mL). The organic phase was washed with a thiosulfate solution (5% w/v, 2×20 mL) and with water 3×40 mL. The organic phase was dried, filtered on a short column of celite and celica (1 cm/4 cm) with a mixture of hexanes:acetone as the eluent. Evaporation of the solvent gave the title compound (95%) as an oil, which was used without further purification at the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=[N:3]1.[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C=O)C>[CH3:1][N:2]1[C:6]([CH:7]([CH2:19][CH:18]=[CH2:17])[C:8]([O:10][CH3:11])=[O:9])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=[N:3]1
Reactant: COC(=O)Cc1c([N+](=O)[O-])cnn1C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(C(=O)OC)c1c([N+](=O)[O-])cnn1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
To a solution of methyl 2-(2-methyl-4-nitro-pyrazol-3-yl)acetate (869 mg, 4.36 mmol) in anhydrous DMF (10 mL) was added at 0° C. sodium hydride (218 mg, 5.45 mmol, 60 mass %), the mixture became dark red right away. After stirring at 0° C. for 15 min, allyl bromide (0.57 mL, 6.54 mmol) was added slowly, stirred at 0° C. for 10 min then room temp for 1 h. The reaction was quenched with water (20 mL) and extracted with EA (200 mL, 50 mL). Combined organic layer was washed with water (15×3 mL), brine (10 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified via silica gel chromatography (0-100% EtOAc/heptane) to afford methyl 2-(2-methyl-4-nitro-pyrazol-3-yl)pent-4-enoate (713 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 5.71-5.54 (m, 1H), 5.01 (d, J=13.1 Hz, 2H), 4.43 (dd, J=9.8, 5.5 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 3.14-3.02 (m, 1H), 2.79-2.62 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:27][CH3:28])=[C:11](/[C:14](/[CH3:26])=[CH:15]\[CH:16]=[CH:17]\[C:18](\[CH3:25])=[CH:19]\[C:20]([O:22]CC)=[O:21])[CH:12]=2)[O:7][C:6]([CH3:30])([CH3:29])[CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:27][CH3:28])=[C:11](/[C:14](/[CH3:26])=[CH:15]\[CH:16]=[CH:17]\[C:18](\[CH3:25])=[CH:19]\[C:20]([OH:22])=[O:21])[CH:12]=2)[O:7][C:6]([CH3:30])([CH3:29])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(cc1/C(C)=C\C=C\C(C)=C\C(=O)O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure G, ethyl 7-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-methyl-octa-2E,4E,6Z-trienoate (Compound 33, 60 mg, 0.15 mmol) was hydrolyzed with 1 M NaOH. Purification by column chromatography (silica gel, 30% ethyl acetate in hexanes) followed by recrystallization from acetonitrile yielded the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:6]2[C:7]3[CH2:8][CH2:9][N:33]([C:30]4[CH:29]=[N:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=4)[C:2]=3[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Reactant: COc1ccc(N)cn1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(OC)nc2)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 2-methoxy-pyridin-5-ylamine, the desired compound was obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[N:46]([CH2:49][CH3:50])=[C:47]=[O:48]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:45]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([C@@H:40]1[CH2:44][CH2:43][N:42]([C:47]([NH:46][CH2:49][CH3:50])=[O:48])[CH2:41]1)=[O:39]
Reactant: CCN=C=O
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)N1CC[C@@H](C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using (3R)—N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and isocyanato-ethane as starting materials in 40% yield. LCMS for C26H29ClN7O2 (M+H)+: m/z=506.2.
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[CH:13]([C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:17]=1[NH2:18])([CH3:15])[CH3:14]>C(OCC)(=O)C>[CH:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:16]([CH:13]([CH3:15])[CH3:14])[C:17]=1[N:18]1[C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2][C:1]1=[O:12])([CH3:25])[CH3:24]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)Cc2ccccc2C1=O
Reaction time: 1 h
Yield: 36 %

Procedure:
0.512 g (3.16 mmol) of homophthalic anhydride and 0.42 g (2.37 mmol) of 2,6-diisopropylaniline were mixed, and melted at a temperature of 200° C. for 1 hour. The reactant was dissolved in ethyl acetate, washed with aqueous NaHCO3 solution, with water and then with saturated aqueous sodium chloride, dried over anhydrous MgSO4, and subjected to filtration with a folded filter paper. The filtrate was concentrated and evaporated to dryness. The residue was recrystallized by using a mixture of CH2Cl2 and hexane, to obtain 0.351 g (yield 36%) of the specified substance as light purple leaflets. It showed the following physical properties and analyzed values.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][NH:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]3[CH2:24][CH2:23][CH:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[CH:14]=2)[CH:9]=1)C.[OH-].[Li+].Cl>CO>[C:25]([C@H:22]1[CH2:21][CH2:20][C@H:19]([O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[C:8]([CH2:7][NH:6][CH2:5][C:4]([OH:29])=[O:3])[CH:17]=[CH:16]3)[CH2:24][CH2:23]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)CNCc1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCC(=O)O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-acetic acid ethyl ester (60 mg, 0.15 mmol) in methanol (1 mL) was added aqueous lithium hydroxide (4.2 M, 0.5 mL, 2 mmol) to form a white precipitate. The mixture slurry was stirred at room temperature for 3 hrs then at 50° C. for 2 hrs. The slurry was neutralized with 1 N HCl to pH 6 and the white precipitate was filtered and dried under vacuum to give white precipitate (48 mg, yield: 86%). ESI-MS: 392.3 (M+23)+; 1H NMR (400 MHz, DMSO) δ=7.77-7.82 (m, 3H), 7.48 (dd, 1H), 7.37 (d, 1H), 7.15 (dd, 1H), 4.38 (m, 1H), 4.07 (s, 2H), 3.16 (s, 2H), 2.20 (d, 2H), 1.82 (d, 2H), 1.35 (m, 2H), 1.10-1.25 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: [CH3:1][C:2](=O)[C:3](=O)[CH3:4].[NH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH2:17]>C(#N)C>[CH3:1][C:2]12[C:3]3([CH3:4])[N:14]([CH2:13][CH2:12][CH2:11][N:10]3[CH2:9][CH2:8][NH:7]1)[CH2:15][CH2:16][NH:17]2
Reactant: CC(=O)C(C)=O
Reactant: NCCNCCCNCCN
Solvent: CC#N
Product: CC12NCCN3CCCN(CCN1)C32C

Procedure:
A solution of 5.37 g (62.4 mmol) of butanedione in 30 ml of acetonitrile is slowly added dropwise to a solution of 10.00 g (62.4 mmol) of commercial N,N′-bis (2-aminoethyl)-1,3-propanediamine in 100 ml of acetonitrile at 0° C. The mixture is maintained at this temperature for two hours. After evaporating the solvent, compound 1 is isolated quantitatively in the form of a yellow solid and is used for the following stage without subsequent purification.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])C=CC=CC=1.CC(C)([O-])C.[K+].[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[F:12][C:11]([F:14])([F:13])[CH2:10][CH:9]=[C:43]1[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:41][CH2:42]1
Reactant: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CCC(F)(F)F)CC1
Reaction time: 0.25 h
Yield: 177.2 %

Procedure:
To a solution of triphenyl(3,3,3-trifluoropropyl)phosphanium bromide (Intermediate 213, 972 mg, 2 mmol) in THF (20 mL) at 0 C under nitrogen was added potassium tert-butoxide (235 mg, 2.1 mmol). The resulting reaction mixture was stirred at 0 C for 15 min and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (398 mg, 2 mmol) in THF (5 mL) was added. The solution was stirred for a further 1 h at 0 C and then evaporated to dryness. The resulting residue was dissolved in EtOAc (25 mL) and washed with water (2×25 mL). Combined organics were washed with brine, dried over magnesium sulfate and evaporated to dryness. The crude solid was dissolved in diethyl ether (50 mL) and then filtered to remove insoluble impurities. The filtrate was evaporated to dryness to afford tert-butyl 4-(3,3,3-trifluoropropylidene)piperidine-1-carboxylate (Intermediate 212, 0.99 g, triphenylphosphine detected as impurity) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH:19]([Mg]Br)=[CH2:20].[Cl-].[NH4+]>O1CCCC1>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17])[CH:19]=[CH2:20]
Reactant: C=C[Mg]Br
Reactant: COCOCC(C)=CCCC(C)=CCCC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(C)(O)CCC=C(C)CCC=C(C)COCOC
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A solution of 6,10-dimethyl-11-(methoxymethyl)oxy-5,9-undecadien-2-one (60 mg, 0.24 mmol) in tetrahydrofuran (2 ml) was stirred on an ice bath under argon atmosphere. To the solution was added vinylmagnesium bromide in tetrahydrofuran (1.0 ml, 1.0 mmol, 1.0M), and the mixture was warmed to room temperature and stirred for 4 hours. After addition of saturated aqueous ammonium chloride (2 ml), the reaction mixture was extracted with ether. The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a crude product, which was purified with silica gel column chromatography to obtain 3,7,11-trimethyl-12-(methoxymethyl)oxy-1,6,10-dodecatrien-3-ol (54 mg, 80%).