Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([NH:16][CH3:17])=[O:15])[C:7]2=[O:12].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([CH3:32])[C:29](O)=[O:30])=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C@H:28]([CH3:32])[C:29]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([NH:16][CH3:17])=[O:15])[C:7]3=[O:12])=[O:30])=[CH:26][CH:27]=1
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Reactant: CNC(=O)[C@@H](C(C)C)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)[C@@H](C(C)C)n1ccc2c(NC(=O)[C@@H](C)c3ccc(Cl)cc3)cccc2c1=O

Procedure:
(R)-2-(5-Amino-1-oxoisoquinolin-2(1H)-yl)-N,3-dimethylbutanamide (0.2 g, 0.0007 mol), (S)-2-(4-chlorophenyl)propanoic acid (0.16 g, 0.00088 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.56 g, 0.0015 mol), N,N-diisopropylethylamine (0.4 g, 0.003 mol) were stirred in methylene chloride (3 mL, 0.05 mol) and N,N-dimethylformamide (1 mL, 0.01 mol) at room temperature over a weekend. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with NaHCO3 (20 mL×3), dried over Na2SO4, purified via flash chromatography (12 g of silica gel, 0-90% EtOAc/Hexane), and then prep. HPLC yielded a white solid. 1H NMRδ (CDCl3) δ: 9.23 (d, J=8.1 Hz, 1H), 8.00 (t, J=7.5 Hz, 1H), 7.52-7.36 (m, 6H), 7.04 (br, 1H), 6.17 (br, 1H), 6.03-6.00 (m, 1H), 5.07 (d, J=11.4 Hz, 1H), 3.82 (q, J=7.0 Hz, 1H), 2.76 (d, J=4.8 Hz, 3H), 2.56-2.48 (m, 1H), 1.65 (dd, J=1.8, 7.1 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H), 0.75 (dd, J=2.6, 6.6 Hz, 3H). MS m/z 440.0 (M+H)+.
Reaction SMILES: [SH3+:1].[Br:2][CH:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4]1.O.[Na].[CH3:16]S>C(O)C>[Br:2][CH:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4]1.[CH3:16][S:1][CH:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4]1
Reactant: [SH3+]
Reactant: CS
Agent: O=C1c2ccccc2OCC1Br
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CSC1COc2ccccc2C1=O

Procedure:
The sulfonium salt compound expressed by structural formula [6] was synthesized as follows. First, the present inventor prepared 3-bromo-4-chromanone. The 3-bromo-4-chromanone was synthesized in accordance with the report by W. S. Johnson et. al. in J. Am. Chem. Soc., vol. 66, pages 218-220, 1944. 10.4 grams of 3-bromo-4-chromanone was dissolved in 42 milli-litters of ethanol. 21.3 milli-litters of 15% water solution of methyl-mercaptan sodium salt was dropped thereinto. The resultant solution was agitated at room temperature for 2 hours, and the resultant mixture was poured into cold water. An organic layer was extracted by using 200 milli-litters of ether, and the ether layer was washed in sodium chloride and, thereafter, water. The ether layer was dried by using magnesium sulfate, and the solvent was removed in low pressure. The residue was put in a silica gel column. Using eluate containing hexane and ethyl acetate at 3:1, the residue was separated and refined. Then, 1.52 grams of 3-methylthio-4-chromanone was obtained. The yield was 17%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:12].CS(C)=O>CCOCC>[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)[CH3:12]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC1CCNCC1
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)CC1CCN(c2ccc(C(C)=O)cc2)CC1
Temperature: 150 °C

Procedure:
A microwave vial was charged with 4′-fluoroacetophenone (1.2 Ml, 10.4 mmol, 1.0 equiv) and 2-(piperidin-4-yl)-acetic acid ethyl ester (3.5 g, 20.7 mmol, 2.0 equiv) in 20 Ml DMSO. The homogeneous reaction was heated to 150° C. for 20 min. The cooled reaction was then diluted with ether and washed sequentially with saturated ammonium chloride, water, and brine. The organic extracts were then dried over sodium sulphate, filtered, and concentrated in vacuo. Purification by flash chromatography (10-40% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.07 Hz, 3 H) 1.47 (d, J=12.13 Hz, 2 H) 1.62 (br.s., 1 H) 1.90 (d, J=12.63 Hz, 2 H) 2.04-2.15 (m, J=11.18, 11.18, 7.45, 7.45, 3.79, 3.66 Hz, 1 H) 2.33 (d,J=7.07 Hz, 2 H) 2.57 (s, 3 H) 2.97 (td, J=12.57, 2.15 Hz, 2 H) 3.93 (d, J=12.88 Hz, 2 H) 4.20 (q, J=7.07 Hz, 2H) 6.96 (d, J=6.82 Hz, 2 H) 7.92 (d, J=9.09 Hz, 2 H); (M+H)+ 290.1.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][C:5]1[CH:27]=[CH:26][CH:25]=[CH:24][C:6]=1[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][N+](C)(C)C)=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1>C(O)C#C>[CH3:4][C:5]1[CH:27]=[CH:26][CH:25]=[CH:24][C:6]=1[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][O:8][CH2:7][C:6]#[CH:5])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccccc1COc1cccn2c(C[N+](C)(C)C)c(C)nc12
Agent: C#CCO
Agent: [H-]
Agent: [I-]
Product: C#CCOCc1c(C)nc2c(OCc3ccccc3C)cccn12
Temperature: 0 °C
Yield: 110.8 %

Procedure:
To a solution of sodium hydride (63.6% in mineral oil dispersion, 0.285 g) in 2-propynyl alcohol (12 ml) was added 8-(2-methylbenzyloxy)-3-trimethylammoniomethyl-2-methylimidazo[1,2-a]pyridine iodide (3 g) and the mixture was heated at 85°-100° C. for 1.5 hours. After being cooled, the mixture was poured into ice-water and the resulting precipitate was collected by filtration and dissolved in methylene chloride. The solution was treated successively with silica gel (4.5 g) and activated charcoal and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of ethyl acetate and petroleum ether to give 8-(2-methylbenzyloxy)-3-(2-propynyloxymethyl)-2-methylimidazo[1,2-a]pyridine (1.18 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].[CH3:14][C:15]([CH3:17])=O>C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>[CH3:14][C:15]1([CH3:17])[O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[C:11](=[O:13])[O:12]1
Reactant: O=C(O)c1ccc(O)c(C(=O)O)c1
Reactant: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)c2cc(C(=O)O)ccc2O1
Temperature: 100 °C
Yield: 77 %

Procedure:
A suspension of 4-hydroxyisophtalic acid (Aldrich, 5.0 g, 27.5 mmol) in acetone (10 mL), TFA (30 mL) and TFAA (10 mL) was heated at 100° C. for 24 hrs. The reaction mixture was concentrated under reduced pressure. The residue was taken up with an aqueous solution of HCl (100 mL, 1N) and extracted with EtOAc (3×200 L); The combined organic layers were dried over MgSO4 and the solvents were removed under reduced: pressure. The crude compound was recrystallized in Et2O (50 mL) to give 4.67 g (77%) of the title compound as a beige powder. 1H NMR (DMSO-d6) δ: 8.37 (d J=1.9 Hz, 1H), 8.19 (dd, J=2.2 and 8.7 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 1.72 (s, 6H). HPLC, Rt: 2.40 min (purity: 95.7%).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH:9]1[C:18]2[C:13](=[C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1.CN(P(N(C)C)(N(C)C)=O)C.CI>C1COCC1>[CH:9]1[C:18]2[C:13](=[C:14]([CH:19]([CH3:1])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1cccc2cnccc12
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)c1cccc2cnccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide (12.75 mL, 2M, 25.5 mmol) in THF (160 mL) at −78° C. under nitrogen was treated with ethyl 5-isoquinolinylacetate (5.00 g, 23.2 mmol) in THF (5 mL). After stirring for 30 minutes at −78° C., the mixture was treated with HMPA (5.2 mL) and methyl iodide (1.62 mL, 25.5 mmol). After stirring for 30 minutes at −78° C., the mixture was warmed to 0° C. over 1 hour and quenched by addition of saturated NH4Cl solution. The mixture was concentrated under reduced pressure to a volume of ˜10 mL, diluted with ethyl acetate (200 mL), washed with water (100 mL×5), washed with brine, dried with anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 230 (M+H)+; MS (ESI−) m/z 228 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.53 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.47 (q, J 7.1, 1H), 7.18 (m, 2H), 7.70 (m, 3H), 8.05 (m, 2H), 8.53 (d, J 6.1, 1H), 8.68 (t, J 6.8, 1H), 9.32 (s, 1H); Anal. Calcd for C20H16F4N2O+1.25HCl: C, 56.93; H, 4.12; N, 6.64. Found: C, 56.72; H, 4.45; N, 7.03.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH:23][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)[N:3]=3)=[CH:21][C:20]=2[O:19]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Reactant: Nc1ccc2c(c1)OCO2
Product: FC(F)(F)c1cc(Nc2ccc3c(c2)OCO3)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4-methylenedioxyaniline (53 mg, 0.386 mmol) similar to Example 58 and isolated as a dark brown solid (47 mg, 68%). 1H NMR (CDCl3): 8.77 (dd, J=1.5, 4.5 Hz, 2H), 8.26 (dd, J=1.5, 4.5 Hz, 2H), 7.06 (s, 1H), 6.93 (s, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.81 (dd, J=2.1, 8.1 Hz, 1H), 6.81 (s, 1H), 6.06 (s, 2H).
Reaction SMILES: [S:1]([C:19]1[CH:24]=[C:23]([C:25]2[C:26]([C:30]([F:33])([F:32])[F:31])=[N:27][NH:28][CH:29]=2)[CH:22]=[CH:21][C:20]=1[C:34]#[N:35])[C:2]1C=C(C2C(C(F)(F)F)=NNC=2)C=CC=1C#N.C(S([O-])=O)O.[Na+].C(=O)([O-])[O-].[K+].[K+].[F:48][C:49]([F:53])([F:52])CI>CN(C)C=O.O>[F:48][C:49]([F:53])([F:52])[CH2:2][S:1][C:19]1[CH:24]=[C:23]([C:25]2[C:26]([C:30]([F:32])([F:33])[F:31])=[N:27][NH:28][CH:29]=2)[CH:22]=[CH:21][C:20]=1[C:34]#[N:35]
Reactant: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1Sc1cc(-c2c[nH]nc2C(F)(F)F)ccc1C#N
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Yield: 142.3 %

Procedure:
2.7 g (5.0 mmol) of 1,1′-thiodi-[2-cyano-5-(3-trifluoromethylpyrazolyl)benzene], 3.0 g (19.5 mmol) of Rongalite, 3.0 g (21.7 mmol) of potassium carbonate and 6.1 g (29.0 mmol) of 2,2,2-trifluoroethyl iodide were stirred in 50 ml of N,N-dimethylformamide at room temperature for 3 hours. The resulting reaction mixture was poured into 300 ml of water and extracted with 50 ml of ethyl acetate twice. The ethyl acetate layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 2.5 g of 2-(2,2,2-trifluoroethylthio)-4-(3-trifluoromethylpyrazolyl)benzonitrile (yield 71.4%) as a brown solid (m.p. 65-67° C.).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]5[O:26][CH2:25][CH2:24][C:23]=5[CH:27]=4)[CH:18]=[C:13]3[C:12]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO>[O:26]1[C:22]2[CH:21]=[CH:20][C:19]([C:17]3[CH:18]=[C:13]4[C:12]([C:28]5[CH:32]=[N:31][NH:30][CH:29]=5)=[CH:11][NH:10][C:14]4=[N:15][CH:16]=3)=[CH:27][C:23]=2[CH2:24][CH2:25]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2cc(-c3ccc4c(c3)CCO4)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1cc2c(cc1-c1cnc3[nH]cc(-c4cn[nH]c4)c3c1)CCO2
Temperature: 85 °C
Yield: 52.9 %

Procedure:
To 49 (45 mg, 0.10 mmol) in EtOH (3 mL) was added 10% aq. NaOH (1.25 mL) and the reaction mixture was heated at 85° C. for 1 h. The mixture was concentrated to afford a yellow solid. Purification by preparative LCMS (column LUNA 10μ C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) afforded the product 50 (16 mg, 53%) as a white solid; 1H NMR (400 MHz, CD3OD) δ 3.24 (t, J=17.4, 8.7 Hz, 2H), 4.55 (t, J=17.4, 8.7 Hz, 2H), 6.80 (d, J=8.2 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.50 (s, 1H), 7.58 (s, 1H), 7.98 (s, 2H), 8.24 (s, 1H), 8.38 (s, 1H).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[C:46]([NH2:53])=[C:45]([Cl:54])[CH:44]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:55]=[CH:56][CH:57]=[CH:58][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:51])([F:50])[F:52])[C:46]([NH2:53])=[C:45]([Cl:54])[CH:44]=3)[C:21]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:30][CH2:31][CH:32]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:33][CH2:34]4)[CH2:27][CH2:28]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:55]=[CH:56][CH:57]=[CH:58][C:6]=2[NH:5]1
Reactant: CCOC(=O)CCC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(CCC(=O)O)CC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2.40 mg (0.10 mmol) LiOH in 1 mL water was added to 50 mg (0.06 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(2-ethoxycarbonyl-ethyl)-1,4′-bipiperidinyl-1′-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 3 mL THF and the reaction mixture was stirred for 4 h at RT. THF was eliminated in a nitrogen stream, the residue was taken up in a little water and purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[C:12]([C:13]#[N:14])=[CH:11][C:10]([F:15])=[C:9]([Cl:16])[N:8]=1>>[Cl:6][C:7]1[N:8]=[C:9]([Cl:16])[C:10]([F:15])=[CH:11][C:12]=1[C:13]([NH2:14])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Product: NC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 75 °C

Procedure:
The amide was prepared by addition of concentrated sulfuric acid, 185 kg, to the 2,6-dichloro-3-cyano-5-fluoropyridine (2) residue prepared in Example 2b. The mixture was heated at about 75° C. for 1 hour. The solution was cooled and added to 360 kg of ice water. The suspension formed was extracted with isopropyl alcohol/chloroform (30:70). The organic layer was removed and dried. The solvent was evaporated to provide the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.C(N(CC)CC)C.[F:31][C:32]([F:40])([C:36]([F:39])([F:38])[F:37])[C:33](Cl)=[O:34].Cl>CN(C)C1C=CN=CC=1.ClCCl.CCOCC>[F:31][C:32]([F:40])([C:36]([F:39])([F:38])[F:37])[C:33]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)=[O:34]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)C(F)(F)C(F)(F)F)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
To an ice-cooled, stirred mixture of 3α-hydroxy-5α-pregnan-20-one (260 mg, 318.5 g/m, 0.82 mmol), triethylamine (0.17 mL), and 4-dimethylaminopyridine (DMAP catalytic, 10 mg, 122.17 g/m, 82 umol) dissolved in 17 mL of dry dichloromethane under a nitrogen atmosphere was added pentafluoropropionyl chloride (168 mg, 182.5 g/m 0.92 mmol). The reaction was stirred at 0° C. for 10 hours and then poured into 100 ml of 10% HCl and 200 ml of ether. The organic phase was washed once more with acid, twice with saturated sodium bicarbonate, and then dried over magnesium sulfate. After removal of solvent in vacuo, the crude product was purified by filtration through a bed of silica gel with hexane/ethyl acetate (15:35) elution. The product was isolated from the two earliest fractions (100 mL each) to give (330 mg, 464.5 g/m, 0.71 mmol, 87%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)=[CH:5][CH:4]=1.Br[C:21]1[CH:22]=[CH:23][C:24]2[C:25]3[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32][CH2:31][C:26]=3[N:27]([CH3:30])[C:28]=2[CH:29]=1>>[CH3:30][N:27]1[C:28]2[CH:29]=[C:21]([N:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=4)=[CH:12][C:13]3=[O:17])[CH:22]=[CH:23][C:24]=2[C:25]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32][CH2:31][C:26]1=2
Reactant: O=c1cc(OCc2ccc(C(F)(F)F)nc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)nc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 40.1 %

Procedure:
4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (177 mg, 0.655 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.54 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (120 mg, 40%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.28 (m, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.06-6.04 (m, 2H), 5.16 (s, 2H), 4.65-4.60 (br m, 2H), 3.89-3.79 (br m, 2H), 3.63 (s, 3H), 2.87-2.78 (br m, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10]([O:15][CH3:16])(=[O:14])[C:11]([CH3:13])=O>C1C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[CH3:13][C:11](=[N:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[C:10]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C)=O
Reactant: Cc1cccc(C)c1N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: COC(=O)C(C)=Nc1c(C)cccc1C

Procedure:
A solution of 2,6-dimethyl aniline (37.2 ml; 0.3 mol) in benzene (200 ml) was added with 0.5 g of ZnCl2, and, dropwise at room temperature, with 33.2 ml (0.33 mol) of methyl pyruvate.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:18]=[CH:17][C:8]2[CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[O:11][C:7]=2[CH:6]=1)(=[NH:4])[NH2:3].[OH-].[Na+]>>[ClH:1].[C:2]([C:5]1[CH:18]=[CH:17][C:8]2[CH:9]=[C:10]([C:12]([OH:14])=[O:13])[O:11][C:7]=2[CH:6]=1)(=[NH:3])[NH2:4]
Reactant: CCOC(=O)c1cc2ccc(C(=N)N)cc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)c1ccc2cc(C(=O)O)oc2c1
Yield: 56.3 %

Procedure:
Ethyl 6-amidino-2-benzofurancarboxylate hydrochloride (129 mg, 0.480 mmol) was hydrolyzed with a 1N aqueous sodium hydroxide solution to give 65 mg of 6-amidino-2-benzofurancarboxylic acid hydrochloride as a brown solid (56%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]1[C:6]=2[N:7]=[CH:8][C:9]([OH:16])=[CH:10]1.Br[CH2:18][CH2:19][CH2:20][CH3:21].[H-].[Na+]>>[CH2:18]([O:16][C:9]1[CH:8]=[N:7][C:6]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[C:14]1[C:5]=2[N:4]=[CH:3][C:2]([O:1][CH2:3][CH2:2][CH2:15][CH3:14])=[CH:15]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCBr
Reactant: Oc1cnc2c(ccc3cc(O)cnc32)c1
Agent: [H-]
Agent: [Na+]
Product: CCCCOc1cnc2c(ccc3cc(OCCCC)cnc32)c1

Procedure:
3,8-dibutoxy-1,10-phenanthroline was synthesized from 3,8-dihydroxy-1,10-phenanthroline hydrobromate and 1-bromobutane using sodium hydride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH:30][C@@H:31]([CH3:35])[C:32](O)=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:32](=[O:33])[C@@H:31]([OH:30])[CH3:35])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: C[C@H](O)C(=O)O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)[C@H](C)O)c1

Procedure:
Prepared as described in Example 110 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 39 mg, 1000 μmol) and (2S)-2-hydroxypropanoic acid (18 mg, 20 μmol). Yield 17 mg (37%).
Reaction SMILES: [CH2:1]([C@@:8]12[CH2:20][CH2:19][CH2:18][N:9]1[C@@H](C(Cl)(Cl)Cl)[O:11][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:21]>CO>[CH2:1]([C@@:8]1([C:12]([NH2:21])=[O:11])[CH2:20][CH2:19][CH2:18][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12Cc1ccccc1
Solvent: CO
Product: NC(=O)[C@]1(Cc2ccccc2)CCCN1
Temperature: 50 °C

Procedure:
A mixture of (3R,7aR)-7a-benzyl-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1one (1.40 g, prepared as described by Wang and Germanas Synlett 1999, 33-36.) and 7 M ammonia in MeOH (15 ml) was heated at 50° C. for 3 days in a sealed vessel. The cooled RM was then evaporated and triturated with chloroform to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]#[N:16].[Cl-].[Ca+2].[Cl-]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]#[N:16])=[CH:4][CH:3]=1
Reactant: N#CC1CCCC1=O
Reactant: Nc1ccc(F)cc1
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2ccc(F)cc2)CCC1

Procedure:
4-Fluoro-aniline (Aldrich Chemicals) (2.3 g, 21 mmol), cyano-ketone (Example 11) (2.2 g, 20 mmol), calcium chloride (2.5 g, 23 mmol) and T.H.F. (30 ml) were heated under reflux for 21 hours. After being allowed to cool, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (160° C., 0.4 mm Hg) gave the product as an off-white powder.