Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].C([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH2:35])[CH:33]=2)[CH:28]=[N:27]1)(OC(C)(C)C)=O>>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH:35][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[CH:33]=2)[CH:28]=[N:27]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc2cn[nH]c2c1
Temperature: 100 °C
Yield: 5.6 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and 280 mg of 1-Boc-6-aminoindazole in place of the 3-(tert-butyl)aniline. The reaction mixture is concentrated under reduced pressure and taken up in 13 ml of 1,4-dioxane and 3 ml of 1N hydrochloric acid, and is then microwave-heated for 10 minutes at 100° C. After cooling to ambient temperature, the reaction mixture is concentrated under reduced pressure and taken up in 30 ml of water, and then a saturated aqueous solution of sodium bicarbonate is added so as to obtain a pH in the region of 8. The precipitate formed is filtered off and washed with water, ethyl acetate and ethyl ether. After purification by silica column chromatography, elution being carried out with a gradient of the eluent CH2Cl2/MeOH: 70/30 in dichloromethane of 0% to 100%, 20 mg of N-(1H-indazol-6-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](SC)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[N:16]1)(=O)C1C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1)[NH2:30].Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:26][C:27]1[CH:28]=[C:29]([NH:30][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[N:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:31]=[CH:32][C:33]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:43])([F:44])[F:42])[CH:36]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: CSc1ncnc2cnn(CCOCCOC(=O)c3ccccc3)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: OCCOCCn1ncc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 140 °C
Reaction time: 33.5 h
Yield: 11.1 %

Procedure:
A mixture of 2-{2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethoxy}ethyl benzoate (328 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (264 mg), pyridine hydrochloride (159 mg) and 1-methyl-2-pyrrolidone (7.5 mL) was stirred at 140° C. for 33.5 hrs. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (15 mL), and extracted with ethyl acetate (35 mL×2). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100). The object fraction was concentrated under reduced pressure and the residue was dissolved in methanol (5 mL). 1N Aqueous sodium hydroxide solution (1 mL) was added and the mixture was stirred at room temperature for 2 hrs. After concentration of the reaction mixture under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) and recrystallized from ethyl acetate-hexane to give the title compound (50 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10](C)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][S:13]([NH2:16])(=[O:15])=[O:14].[CH2:17](N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[NH2:1][C:2]1([CH3:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[C:4]([NH:16][S:13]([CH3:12])(=[O:15])=[O:14])=[O:6]
Reactant: CS(N)(=O)=O
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(N)C=CC=CC1C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
20 g (128 mmol) of 2-amino-3-methylbenzoic acid are dissolved in 600 ml of dichloromethane, and 10.98 g (115 mmol) of methanesulphonamide, 24.40 g (154 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 15.68 g (128 mmol) of 4-(dimethylamino)pyridine are then added under argon. The reaction is stirred at room temperature for 16 h, the solvent is distilled off and the residue is taken up in ethyl acetate and water. The ethyl acetate phase is washed four times with a 1N hydrochloric acid solution and then in each case once with water and a concentrated sodium chloride solution. After drying over sodium sulphate, the desired product is obtained by chromatographic purification.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH3:12].[C:14]([O-:17])(=[O:16])[CH3:15].[Na+].CN(C)C=O.CCCCCC>C(OCC)(=O)C>[C:14]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH3:12])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: CCC/C=C/CCCCCCCBr
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC/C=C/CCCCCCCOC(C)=O
Temperature: 110 °C
Yield: 72.3 %

Procedure:
Z/E-8-dodecenyl bromide (520 mg, 2.2 mmol), prepared as described above, was weighed into a 50 mL round bottom flask with a magnetic stir bar. Sodium acetate (540 mg, 6.6 mmol), freshly fused, was added in a single portion, followed by dimethyl formamide (5 mL). The flask was equipped with a condenser and was placed in a preheated oil bath (55° C.). The oil bath was further heated to 110° C. over 3 hours. The progress of the reaction was monitored by thin layer chromatography (TLC) using hexane:ethyl acetate in a ratio of 9:1 as the eluant. After 5 hours the reaction mixture was removed from the heat and allowed to cool to ambient temperature. Water (10 mL) was added to dilute the reaction mixture, and the resulting aqueous phase was extracted with hexane (3×15 mL). The combined hexane extracts were washed with water (2×10 mL) and brine (10 mL). The resulting organic phase was dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to yield the Z/E-8-dodecenyl acetate product as a clear liquid (360 mg, 73%). The Z/E ratio was determined to be 92:8 by gas chromatography (GC) using a DB-XLB column.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([C:18]([O:20]C)=[O:19])=[N:10]2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([C:18]([OH:20])=[O:19])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc(C(=O)OC)n(-c2ccc(OC)cc2)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(C(=O)O)nn1-c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To a solution of dimethyl 1-[(4-methoxy)phenyl]pyrazole-3, 5-dicarboxylate (32.7 g, 110 mmol) in 50 mL of dioxane and 100 mL of water was added concentrated sulfuric acid (1.50 mL, 28.2 mmol). The resulting solution was stirred at 100° C. for 18 h and then cooled to room temperature. The reaction was made basic with potassium carbonate and then extracted with ether to remove unreacted diester. The aqueous layer was acidified with HCl and was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4) and concentrated to afford 19.2 g (63%) of the title compound along with 5.0 g (15%) of unreacted starting material. The title compound was used without further purification. LRMS (ES-): 274.9 (M-H)-.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:11]([Mg]Br)=[CH2:12].[Cl-].[NH4+]>C(OCC)C.O1CCCC1.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH:11]=[CH2:12]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C=CC(O)c1ccc(Cl)cc1Cl

Procedure:
A solution of 20.0 g (114 mmol) of 2,4-dichlorobenzaldehyde in 200 ml of diethyl ether was slowly added dropwise to 137 ml (137 mmol) of a 1N solution of vinylmagnesium bromide in tetrahydrofuran at RT under argon. After heating under reflux for 1 h, the reaction mixture was added to saturated aqueous ammonium chloride solution and diluted with diethyl ether and water. The phases were separated, and the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5/1) to result in 18.8 g (81% of theory) of the title compound.
Reaction SMILES: [CH3:1][O-:2].[Li+].Cl[CH:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]C)[C:6]([O:8][CH3:9])=[O:7].[CH2:24]=O>CS(C)=O>[CH3:24][CH:10]([C:5]1([O:2][CH2:1]1)[C:6]([O:8][CH3:9])=[O:7])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C[O-]
Reactant: CCCCCCCCCCCCCCC(Cl)C(=O)OC
Reactant: C=O
Agent: [Li+]
Solvent: CS(C)=O
Product: CCCCCCCCCCCCC(C)C1(C(=O)OC)CO1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
A suspension of lithium methoxide (0.41 g, 0.011 m) in 10 ml of dry DMSO was treated with a suspension of methyl α-chloropalmitate (3.05 g, 0.010 m) in 10 ml of dry DMSO at 35° C., then with paraformaldehyde (0.300 g, 0.01 m) added portionwise over 81/2 hours. The reaction mixture was stirred at 35° C. for an additional two hours then overnight at room temperature. It was extracted with hexane. Water was added to the DMSO layer and this was extracted twice with hexane. The combined hexane extracts were washed with water, dried and evaporated to a clear oil which crystallized (2.49 g, 84%). Glc analysis of product showed 97.5 percent methyl 2-tetradecylglycidate.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH2:19][C:20](Cl)=[O:21].[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH2:19][C:20]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:21]
Reactant: COc1ccccc1
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)Cc2cc(OC)ccc2OC)cc1
Yield: 57.6 %

Procedure:
To a cooled solution (0° C.) of anisole (1.3 g, 12.4 mmol) and (2,5-Dimethoxyphenyl)acetyl chloride (2.2 g, 10.3 mmol) in dichloroethane (30 ml) was added AlCl3 (1.6 g, 12.4 mmol) and the reaction was stirred for thirty minutes. The reaction was then quenched with 2N HCl and the organic layer was then separated, dried, and concentrated. The resulting oil was taken up into MeOH and a solid crystallized which was collected by filtration to give a white solid (1.7 g, 58%): Mp=108–111° C.; 1H NMR (CDCl3) δ 8.01 (d, 2 H, J=9.0 Hz), 6.92 (d, 2 H, J=8.8 Hz), 6.80–6.70 (m, 3 H), 4.20 (s, 2 H), 3.86 (s, 3 H), 3.75 (s, 3 H), 3.74 (s, 3 H); MS 287 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:23]>ClCCl>[CH3:27][C:26]([CH3:29])([CH3:28])[CH2:25][O:24][C:22]([N:6]1[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])=[O:23]
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: CC(C)(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C=Nc1nc(=O)n(C(=O)OCC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.5 %

Procedure:
To an 8 mL screw-cap vial was added dichloromethane (CH2Cl2; 3 milliliters (mL)), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (100 milligrams (mg), 0.54 millimole (mmol)), triethylamine (Et3N; 120 mg, 1.18 mmol), and 2,2-dimethylpropyl chloroformate (90 mg, 0.60 mmol). After shaking for 1.5 hours (h) at room temperature, the mixture was partitioned between ethyl acetate (EtOAc) and water (H2O). The organic phase was dried over magnesium sulfate (MgSO4), filtered, and evaporated. The crude material was purified by reverse phase chromatography to yield 4-(dimethylamino-methyleneamino)-5-fluoro-2-oxo-2H-pyrimidine-1-carboxylic acid 2,2-dimethyl-propyl ester as a white solid (33 mg, 20%): mp 162-164° C.; 1H NMR (300 MHz, CDCl3) δ 8.77 (s, 1H), 7.93 (d, J=6.6 Hz, 1H), 4.08 (s, 2H), 3.27 (s, 3H), 3.20 (s, 3H), 1.05 (s, 9H); ESIMS m/z 299 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:6]=2[CH:34]=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=4)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:6]=2[CH:34]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2F)=NC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2F)=NC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.3 %

Procedure:
A mixture of [9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-nitro-phenyl)-amine (I-212, 500 mg, 1.05 mmol), stannous chloride dihydrate (1.42 g, 6.3 mmol) and ethyl acetate (15 mL) was refluxed for 28 hours, then cooled to room temperature and allowed to sit overnight. The mustard-yellow reaction mixture was poured onto ˜50 g cracked ice with stirring, and sat. NaHCO3 solution was added to adjust the pH to 8. The mixture was extracted with ethyl acetate (3×100 mL). The extracts were combined, dried (Na2SO4), filtered and evaporated in vacuo to provide N-[9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-benzene-1,4-diamine as an orange/yellow solid (500 mg, 100%) MS m/z=448 (M+H). A solution of this product (50 mg, 0.1 mmol), 4-methylpiperazine-1-carbonylchloride (89 mg, 0.6 mmol), diisopropylethylamine (142 mg, 1.1 mmol), in dioxane (0.5 mL) was submitted to microwave irradiation (300 W) for 60 minutes at 160° C. The reaction solution was cooled to room temperature and slowly poured into a stirring saline solution (10 mL). The resulting precipitate was collected by filtration, washed with water and purified by RP-HPLC(C18, 0 to 100% CH3CN in 0.1% aqueous HCO2H) to yield I-280 as a pale yellow solid (6 mg, 10%) MS m/z=574 (M+H).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:11])([CH3:10])[CH3:9])(=O)=O.FC[C@@H](C)C[N:18]1[C:30]([CH3:32])([CH3:31])[CH2:29][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH:19]1[C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42])=[CH:35][CH:34]=1.[CH:45](N(CC)C(C)C)(C)C>O1CCOCC1>[F:11][C:8]([CH3:10])([CH3:9])[CH2:7][N:18]1[C:30]([CH3:32])([CH3:31])[CH2:29][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH:19]1[C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43][CH3:45])=[O:42])=[CH:35][CH:34]=1
Reactant: C[C@H](CF)CN1C(c2ccc(/C=C/C(=O)O)cc2)c2[nH]c3ccccc3c2CC1(C)C
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc(C2c3[nH]c4ccccc4c3CC(C)(C)N2CC(C)(C)F)cc1
Reaction time: 64 h
Yield: 59.4 %

Procedure:
2-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 1, preparation of starting materials) (389 mg, 1.73 mmol) was added to a solution of (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (racemate) (obtained as described in Example 7, preparation of starting materials) (250 mg, 0.69 mmol) and N,N-diisopropylethylamine (0.453 ml, 2.60 mmol) in 1,4-dioxane (1.25 ml). The mixture was stirred at 95° for 64 hours and then partitioned between DCM (30 ml) and water (30 ml). The aqueous layer was extracted with DCM (20 ml) and the extracts combined with the organic layer. The combined extracts were filtered through a phase-separating paper and evaporated. The residue was purified by flash silica chromatography, elution solvent 153% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (racemate) (178 mg, 59.1%) as a beige solid. The racemic product was purified by preparative HPLC (Chiralpak AD column, 20 μm silica, 50 mm diameter, 250 mm length), Heptane:Ethanol: 80:20. Fractions containing the desired compounds were evaporated to dryness to afford (E)-methyl 3-(4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1, first eluted, 70 mg) and (E)-methyl 3-(4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 2, second eluted, 66 mg). 1H NMR (400 MHz, CDCl3, 30° C.) δ 1.00 (3H, s), 1.13 (3H, d), 1.20 (3H, s), 1.44 (3H, d), 2.57-2.78 (3H, m), 2.93 (1H, dd), 3.80 (3H, s), 5.05 (1H, s), 6.41 (1H, d), 7.13 (1H, ddd), 7.18 (1H, ddd), 7.32 (1H, d), 7.43 (2H, d), 7.51 (2H, d), 7.54 (1H, d), 7.64 (1, s), 7.67 (1H d). m/z: ES+ [M+H]+ 435.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C([OH:29])CCCCCCC/C=C\CCCCCCCC.N1C=CC=CC=1>CCCCCC>[C:2]([OH:9])(=[O:29])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCCCCC
Product: O=C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Nicotinoyl chloride hydrochloride (17.8 g, 0.1 mol) and oleyl alcohol (26.85 g, 0.1 mol) were added into hexane (250 ml). Pyridine (15.8 g, 0.2 mol) was added to the stirred mixture over a period of 10 min, and the reaction mixture was stirred at room temperature for 24 h. Pyridine hydrochloride was removed by filtration and washed with hexane. The combined filtrate was extracted with water, dried over MgSO4 and evaporated to dryness. The residue was digested twice with acetonitrile, and the sticky residue was dried to give a clear water-like liquid which turned soap-like upon cooling (21.1 g, 56.5 mmol, 56.5%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[CH:2].CCOC(C)=O>CO.[Pd]>[NH2:10][C:6]1[C:7]([F:9])=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=1
Reactant: C#Cc1cc(F)c([N+](=O)[O-])cc1CC(=O)OCC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(N)c(F)cc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
Ethyl 2-(2-ethynyl-4-fluoro-5-nitrophenyl)acetate (160 mg, 0.64 mmol) was dissolved in MeOH (5 mL) and EtOAc (5 mL) and then Pd—C (20 mg) was added. The reaction mixture was shaken in a Parr hydrogenator (46 psi) overnight at RT. The reaction mixture was filtered, washed with methanol, and concentrated to obtain ethyl 2-(5-amino-2-ethyl-4-fluorophenyl)acetate (135 mg, 93% yield). MS (ESI) m/z: 226.2 (M+H+).
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][NH:14][C@@H:13]([C:17]([OH:19])=O)[CH2:12]1)(OCC1C=CC=CC=1)=O.[Cl:20][C:21]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[C:23](F)[C:22]=1[Cl:31].O.CN(C)C=O>C(N(CC)CC)C>[Cl:20][C:21]1[CH:26]=[C:25]2[C:24](=[CH:23][C:22]=1[Cl:31])[N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C@@H:13]1[C:17](=[O:19])[NH:27]2
Reactant: O=[N+]([O-])c1cc(F)c(Cl)c(Cl)c1
Reactant: O=C(O)[C@H]1CN(C(=O)OCc2ccccc2)CCN1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2cc(Cl)c(Cl)cc2N2CCNC[C@H]12
Temperature: 50 °C
Yield: 157.3 %

Procedure:
To a slurry containing 5.0 g of (R)-4-carbobenzyloxypiperazine-2-carboxylic acid, 4.2 g of 1,2-dichloro-fluoro-5-nitrobenzene, 85 mL of water and 170 mL of dimethylformamide is added slowly 5.3 mL of triethylamine. The solution is heated to 50° C for 5 hours, then at ambient temperature overnight. The dark orange solution is concentrated under reduced pressure (1-2 mm, <50° C.) to an orange oily residue. This oil is dissolved in 400 mL of ethyl acetate and washed with 100 mL of 1 N HCl (2×), with 150 mL of water (2×), and 100 mL of brine. The organic layer is dried over MgSO4, filtered and concentrated to give 8.1 g (94.2%) of title compound as an orange solid foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].O>O1CCCC1>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:18](=[O:19])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc2[nH]ccc2c1)OCC(Cl)(Cl)Cl
Yield: 14.3 %

Procedure:
To a solution of 5-aminoindole (1.00 g, 7.57 mmol) and pyridine (0.720 ml, 9.08 mmol) in tetrahydrofuran (25 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.26 ml, 9.08 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 334 mg (14.3%) of the desired product as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]=[O:17].B(O)(O)O.Cl>CCOCC.CCCCC.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH2:16][OH:17])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Agent: OB(O)O
Solvent: CCOCC
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CO)c(O)c(C(C)(C)C)c1
Temperature: 80 °C

Procedure:
2,4-Di-t-butylphenol (20.63 gr., 0.1 mole), paraformaldehyde (3.0 gr., 0.1 mol), boric acid (6.18 g., 0.1 mol) and toluene (50 ml.) were charged into a flask and heated at 80° C. under nitrogen for 48 hours. The mixture was filtered and the solvent removed to provide a brown oil. This oil was dissolved in ether and stirred with an equal volume of 1 N HCl for 2 hours. The ether layer was removed, washed with water, dried (MgSO4) and evaporated to form a soft yellow solid. This solid was stirred in pentane and then filtered to afford a white solid with a melting point of 97°-99° C. The structure was confirmed by NMR and FD/MS.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].C[O:10][P:11]1[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]1>>[CH:6]([O:5][C:3]([CH2:2][P:11]1(=[O:10])[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]1)=[O:4])([CH3:8])[CH3:7]
Reactant: COP1OC(C)C(C)O1
Reactant: CC(C)OC(=O)CBr
Product: CC(C)OC(=O)CP1(=O)OC(C)C(C)O1
Yield: 94.8 %

Procedure:
Using the procedure of Step A of Example 1, 2.03 g of isopropyl bromoacetate and 1.3 g of 2-methoxy-4,5-dimethyl-1,3,2-dioxaphospholane were reacted to obtain 1.94 g of raw 2-isopropoxycarbonylmethyl-4,5-dimethyl-2-oxo-1,3,2-dioxaphospholane used as is for the next step.