Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N:20]=[C:21]=[O:22].CCCCCC>ClCCCl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[NH:20][C:21]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[O:22]
Reactant: Nc1ccc(I)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: ClCCCl
Solvent: CCCCCC
Product: O=C(Nc1ccc(I)cc1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 0 °C
Yield: 81.6 %

Procedure:
To a solution of 4-iodoaniline (438 mg, 2.0 mmol) in 15.0 mL 1,2-dichloroethane at rt was added 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.304 mL, 2.1 mmol). After 50 minutes 3 mL hexane was added, the mixture cooled to 0° C., the precipitant filtered and rinsed with 10% EtOAc/hexane to give the title compound as a light purple solid (692 mg, 82%). 1H NMR (DSMO-d6) δ: 9.26 (s, 1H), 8.90 (d, J=2.9 Hz, 1H), 8.59 (dd, J=7.3, 2.3 Hz, 1H), 7.60-7.65 (m, 2H), 7.46-7.54 (m, 1H), 7.36-7.43 (m, 1H), 7.29-7.34 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=1>>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=3)=[CH:8][C:7]1=2
Reactant: N#Cc1cc(Br)cs1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3csc(C#N)c3)cc21

Procedure:
The product was prepared, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 4-bromo-2-thiophenecarbonitrile according to the procedure outlined in Example 5, as a yellowish solid: mp 230-231° C. (decomposed); 1H-NMR (CDCl3) δ8.32 (s, 1H, D2O exchangeable), 7.83 (d, 1H, J=1.5 Hz), 7.61 (d, 1H, J=1.4 Hz), 7.43 (dd, 1H, J=8.2, 1.9 Hz), 7.29 (d, 1H, J=1.8 Hz), 6.85 (d,
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:3]1([C:1]#[N:2])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccccn2)CCNCC1
Reaction time: 0.67 h
Yield: 100 %

Procedure:
tert-Butyl 4-cyano-4-pyridin-2-ylpiperidine-1-carboxylate (I-2, 5.45 g, 19 mmol) was dissolved in TFA/CH2Cl2 (1:1, 50 mL) at 0° C. After stirring 40 min, the reaction mixture was concentrated under reduced pressure. The residue was diluted with 2 N NaOH in saturated aqueous NaCl (1:1, 80 mL) and extracted with EtOAc (5×200 mL). The combined extracts were washed with saturated aqueous NaCl, dried (MgSO4), and concentrated under reduced pressure to afford 4-pyridin-2-ylpiperidine-4-carbonitrile (3.55 g, 19 mmol) which was used immediately in subsequent reactions. A solution of 4-pyridin-2-ylpiperidine-4-carbonitrile (3.55 g, 19 mmol) in CH2Cl2 (50 mL) at 0° C. was treated with i-Pr2NEt (10 mL) and n-EtSO2Cl (2,24 mL, 21 mmol). After stirring for 1 h at 0° C., the reaction mixture was treated with 2 N NaOH and stirred vigorously for an additional 1 h, before being extracted with EtOAc (4×200 mL). The combined organic extracts were washed with saturated aqueous NaCl, dried (MgSO4), and concentrated under reduced pressure to afford 1-ethylsulfonyl)-4-pyridin-2-ylpiperidine-4-carbonitrile (I-3) as a yellow-brown solid. Analytical LCMS: single peak (214 nm), 1.6501 min. This material was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:26]([F:29])([F:28])[F:27])=[CH:8][C:9]=2[CH2:11][O:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:4]=[N:3]1.[C:30]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:26]([F:29])([F:28])[F:27])=[CH:8][C:9]=2[CH2:11][O:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16][N:17]([CH3:30])[CH2:18][CH2:19]2)[CH:4]=[N:3]1
Reactant: [BH3-]C#N
Reactant: Cn1ncc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCNCC3)c21
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cnn(C)c23)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-methyl-7-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-1H-indazole (65 mg, 0.161 mmol) and sodium cyanoborohydride (20 mg, 0.322 mmol) in acetonitrile (1 mL) at room temperature was added formalin (50 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 19 mg (28%). 1H-NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H), 7.95 (s, 1H), 7.31 (s, 1H), 7.23 (m, 4H), 7.17 (m, 1H), 4.66 (s, 2H), 3.90 (s, 3H), 3.47 (s, 2H), 2.51 (m, 2H), 2.18 (s, 3H), 2.05-2.25 (m, 4H), 1.91 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 143.7, 139.5, 135.1, 133.8, 128.3, 127.2, 126.2, 124.74, 124.67 (q, J=272 Hz), 124.6, 122.6 (q, J=33 Hz), 121.3, 119.6 (q, J=3.8 Hz), 79.2, 70.6, 51.9, 46.2, 40.6, 38.2, 32.5. Mass spec.: 418.15 (MH)+. Accurate mass spec.: m/z 418.2119 [MH]+, Δ=3.1 ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([P:14]([OH:16])[OH:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.Br[CH2:30][C:31](=[CH2:36])[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([P:14]([CH2:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH2:30])(=[O:15])[OH:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(NC(=O)OCc1ccccc1)P(O)O
Reactant: C=C(CBr)C(=O)OC
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(CP(=O)(O)C(C)NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.8 %

Procedure:
To a stirred solution of 2.25 g (9.3 mmol) of 1-(benzyloxycarbonylamino)ethylphosphonous acid in 70 ml of methylene chloride, were added triethylamine (2.87 ml, 20 mmol), trimethylsilyl chloride (2.60 ml, 20 mmol), and methyl 2-bromomethylacrylate (1.66 g, 9.3 mmol) at 0° C. After stirring at room temperature for 20 hours, the reaction mixture was washed with H2O, 2N HCl, and then saturated NaCl solution and dried over anhydrous magnesium sulfate. The mixture obtained by filtration and evaporation was purified by silica gel chromatography (eluted with chloroform followed by 10% methanol-chloroform) to give 2.50 g (yield 79%) of the product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[CH:27][CH2:28]O)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.S(Cl)([Cl:32])=O>C(Cl)Cl.C(Cl)CCl>[Cl:32][CH2:28][CH:27]=[CH:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[NH:15][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(Nc2ncnc3ccc(C=CCO)cc23)ccc1Oc1cccnc1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(Nc2ncnc3ccc(C=CCCl)cc23)ccc1Oc1cccnc1
Temperature: 100 °C

Procedure:
To a suspension of 0.035 g (0.091 mmol) of 3-{4-[3-methyl-4-(pyridin-3-yloxy) -phenylamino]-quinazolin-6-yl}-prop-2-en-1-ol in 0.5 mL of methylene chloride and 1 mL of ethylene dichloride was added 1 mL of thionyl chloride. The reaction was heated at 100° C. for 1 hour and the solvents were evaporated to provide [6-(3-chloro-propenyl)-quinazolin-4-yl]-[3 methyl-4-(pyridin-3-yloxy)-phenyl]-amine [MS: M+ 403.1] which was dissolved in THF and used directly in the next reaction. To the solution of [6-(3-chloro-propenyl)-quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine was added 0.10 mL of morpholine and 0.044 mL of triethylamine. The mixture was heated at 85° C. for 16 hours, cooled to room temperature, and partitioned between 10% aqueous potassium carbonate and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organics were dried and evaporated to yield 57 mg of material. The product was purified on a silica gel prep plate, eluting with 96:4:0.1 chloroform/methanol/concentrated ammonium hydroxide to afford 26 mg of the title compound; 1H NMR (CDCl3): δ 8.71 (s, 1), 8.33 (m, 2), 7.94 (s, 1), 7.80 (m, 2), 7.69 (s, 1), 7.58 (m, 1), 7.20 (m, 1), 6.94 (d, J=8.7 Hz, 1), 6.68 (d, J=15.8 Hz, 1), 6.46 (m, 1), 3.79 (m, 4), 3.26(m, 2), 2.63 (m, 4), 2.25 (s, 3).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[N:25][OH:26])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2ccc(C(CCC(=O)O)=NO)cc2)cc1
Yield: 93.7 %

Procedure:
In a manner similar to Example 4, Step (c), 4-(4′-tert-butyl-biphenyl-4-yl)-4-oxo-butyric acid (0.277 g, 0.000892 mol) was allowed to react with hydroxylamine hydrochloride (0.0704 g, 0.00101 mol) in the presence of sodium carbonate (0.1074 g, 0.00101 mol) in absolute ethanol (7 mL) to give 0.272 g of 4-(4′-tert-butyl-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a white solid; mp 170.5-171.5° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[CH3:11][O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16].N12CCCN=C1CCCCC2>O1CCCC1>[CH3:11][O:12][C:13](=[O:17])/[CH:14]=[C:15](/[O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[F:1])\[CH3:16]
Reactant: COc1cccc(O)c1F
Reactant: CC#CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)/C=C(\C)Oc1cccc(OC)c1F
Yield: 67.4 %

Procedure:
To a stirred mixture of 2-fluoro-3-methoxy-phenol (3.88 g, 0.027 mol) and methyl-2-butynoate (5.97 g, 0.061 mol) in tetrahydrofuran (30 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.64 g, 0.030 mol) slowly. After addition was complete the mixture was stirred at reflux overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue dried under high vacuum which afforded (E)-3-(2-fluoro-3-methoxy-phenoxy)-but-2-enoic acid methyl ester (4.37 g, 63%) as a colorless oil and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:33]([OH:35])=[O:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=1)=[O:10].C(=O)(O)[O-].[Na+].[C:41]([O:44][CH:45](Cl)[CH3:46])(=[O:43])[CH3:42].O>CN(C=O)C>[C:41]([O:44][CH:45]([O:34][C:33](=[O:35])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:28])([F:29])[F:27])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH3:46])(=[O:43])[CH3:42]
Reactant: Cc1cc(C(F)(F)F)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n1C
Reactant: CC(=O)OC(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.2 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine (145 mg, 0.275 mmol) and sodium bicarbonate (185 mg, 2.2 mmol) in DMF (2 mL) was added 1-chloroethyl acetate (270 mg, 2.2 mmol) at room temperature. The mixture was stirred for 48 h at room temperature. Then, the reaction mixture was poured into water (30 mL) and was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine solution (60 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product, which was purified by silica gel chromatography using a Biotage (40s) column to afford 110 mg (65% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine 1-(acetoxy)ethyl ester as an amorphous white solid. ES-HRMS m/e calcd for C28H25Cl2F3N2O6 (M+Na) 635.0931, found 635.0932.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[F:8][C:9]([F:46])([F:45])[C:10]1[CH:11]=[C:12]([C:20]2[N:24]=[CH:23][N:22](/[CH:25]=[CH:26]\[C:27]([NH:29][NH:30][C:31](=[O:44])[C@@H:32]([NH:36]C(=O)OC(C)(C)C)[CH:33]([CH3:35])[CH3:34])=[O:28])[N:21]=2)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>ClCCl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:36][C@@H:32]([CH:33]([CH3:35])[CH3:34])[C:31]([NH:30][NH:29][C:27](=[O:28])/[CH:26]=[CH:25]\[N:22]1[CH:23]=[N:24][C:20]([C:12]2[CH:11]=[C:10]([C:9]([F:45])([F:46])[F:8])[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=2)=[N:21]1)=[O:44]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 2 %

Procedure:
In a 10 mL round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.25 g, 1.0 eq.) was dissolved in THF (5 mL) and cooled to −60° C. where (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.19 g, 1.3 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.81 mL, 2 eq.) was added dropwise followed by DIPEA (0.48 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (S,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate (0.07 g, yield: 18%). In a 10 mL round-bottom flask, (S,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate was then dissolved in dichloromethane (2 mL). TFA (0.05 mL) was added and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product (0.01 g), which was triturated with petroleum ether and dried under reduced pressure to yield (S,Z)-2-amino-N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-methylbutanehydrazide 2,2,2-trifluoroacetate (0.006 g, yield: 2%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[I:22]I>>[I:22][C:7]1[CH:6]=[C:5]([C:9](=[O:14])[C:10]([F:11])([F:12])[F:13])[CH:4]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:8]=1
Reactant: II
Reactant: O=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(c1cc(I)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 0 °C

Procedure:
To 2.42 g of 3′-trifluoromethyl-2,2,2-trifluoroacetophenone, 6 mL of 30% fuming sulfuric acid and 1.90 g of iodine were added and the resultant mixture was stirred at 50° C. for 5 hours. After the completion of the reaction, the reaction mixture was charged onto 10 g of ice and the resultant mixture was extracted with diethyl ether (20 mL×1). The organic phase was washed with 10 mL of a saturated sodium sulfite aqueous solution and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order, and the solvent was distilled off under reduced pressure to obtain 2.56 g of the objective substance as a light yellow oily substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1>CN1CCCC1=O.O>[C:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:26][CH:25]=1)([CH3:30])([CH3:29])[CH3:31]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(C)(C)Oc1ccc(CCBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(OC(C)(C)C)cc2)CCN(C)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 6.4 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.001 mol) was dissolved in N-methyl 2-pyrolidone (2.0 mL). Powdered potassium hydroxide (0.5 g, 0.0089 mol) was added and heated at 100° C. for 3 h. Reaction mass was cooled to RT and 1-(2-Bromo-ethyl)-4-tert-butoxy-benzene (0.245 g, 0.001 mol) was added at the same temperature and stir for 2 h at RT (TLC showed incomplete reaction). Reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (0.5% MeOH:DCM in neutral alumina, Diameter of column—2.5 cm, Height of alumina—approx. 5 inch) then further purified by preparative TLC to provide the desired compound as light yellow oil (0.024 g, 6% yield). 5-[2-(4-tert-Butoxy-phenyl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.024 g, 0.000063 mol) was dissolved in THF (1.0 mL), A solution of oxalic acid dihydrate (0.008 g, 0.000063 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.020 g, 67% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20]C1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=1[CH3:12])=[O:7]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: Cc1cccc(Nc2ccccc2)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)c2cccc(CCl)c2)c1C
Reaction time: 18 h

Procedure:
To a solution of 3-chloromethylbenzoyl chloride (2.0 g) in methylene chloride (20 mL) was added 2,3- dimethylphenylaniline (1.28 g) and triethylamine (1.47 mL). The solution was stirred 18 h, concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was extracted w/50 mL each of 2% potassium hydrogen sulfate, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo. Upon concentration a precipitated formed which was collected and dried to obtained the product. NMR (300 MHz, DMSO-d6) δ 10.0 (1H, s), 8.02 (1H, s), 7.94 (1H, d, J=7 Hz), 7.63 (1H, d, J=7 Hz), 7.52 (1H, t, J=7 Hz). 7.10 (3H, s), 4.83 (2H, s), 2.27 (3H, s), 2.07 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][SH:43])=[CH:38][CH:37]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH:16]([S:43][CH2:42][C:39]2[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CC=C(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C
Reactant: COc1ccc(CS)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CSC(CC(C)C)C(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 4-(2-tert-butoxycarbonyl-5-methyl-hex-2-enyl)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 5.24 mmol) in DMF (5 mL) was added to a mixture of potassium carbonate (0.54 g, 3.93 mmol) and 4-methoxy-α-toluenethiol (1.17 g, 10.48 mmol) in DMF (50 mL) under nitrogen. The mixture was refluxed for 5 h and allowed to cool to room temperature. The reaction mixture was then poured into H2O and extracted with ethyl acetate. The organic layers were combined and washed with water. The organic layer was dried, filtered and concentrated under reduced pressure to give 3.76 g of crude material. The crude product was purified by column chromatography (ethyl acetate/hexane, 1:10) to give 4-[2-tert-butoxycarbonyl-3-(4-methoxy-benzylsulfanyl)-5-methyl-hexyl]-piperidine-1-carboxylic acid tert-butyl ester (1.77 g, 63%).
Reaction SMILES: [CH2:1]([N:5]1[C:14]([O:15][C@H:16]2[CH2:20][N:19](C(OC(C)(C)C)=O)[C@H:18]([C:28]([O:30][CH3:31])=[O:29])[CH2:17]2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:32])[CH2:2][CH:3]=[CH2:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:5]1[C:14]([O:15][C@H:16]2[CH2:20][NH:19][C@H:18]([C:28]([O:30][CH3:31])=[O:29])[CH2:17]2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:32])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCn1c(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)cc2ccccc2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCn1c(O[C@H]2CN[C@H](C(=O)OC)C2)cc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
A portion of the product from Step 1 (150 mg, 0.34 mmol) was dissolved in CH2Cl2 (4 ml), cooled in an ice bath, and then added TFA (4 ml). The reaction was allowed to warm to room temperature and stir for 1.5 hours. The reaction was concentrated and the resulting oil was partitioned between CH2Cl2 and sated NaHCO3, extracted with CH2Cl2 (2×), combined organics, washed with brine, dried organics over Na2SO4, filtered, concentrated in vacuo to yield the title compound as a oil (113 mg, 97%). LCMS (ES+) m/z 342.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]([NH:14][CH3:15])=[O:13])[C:4]=2[O:3]1.[CH3:17][O:18][P:19]([O:22]C)[O:20][CH3:21]>>[CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[C:8]([P:19]([O:20][CH3:21])([O:18][CH3:17])=[O:22])[CH:9]=[C:10]([O:11][C:12]([NH:14][CH3:15])=[O:13])[C:4]=2[O:3]1
Reactant: COP(OC)OC
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Product: CNC(=O)Oc1cc(P(=O)(OC)OC)cc2c1OC(C)(C)C2
Yield: 26 %

Procedure:
0.1 mole of carbofuran (2,3-dihydro-2,2-dimethyl-7-methylaminocarbonyloxybenzofuran) were reacted with trimethylphosphite analogously to Example 1a. The product was obtained in the form of an oil in a yield of 26%.