Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.O1CCCC1.[CH3:27][NH:28][CH3:29]>O>[CH3:27][N:28]([CH3:29])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(N(C)C)c12
Temperature: 100 °C
Yield: 97.2 %

Procedure:
4-Chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.00 g, 3.39 mmol) was added to a 2M dimethylamine tetrahydrofuran (5.00 mL, 10.0 mmol) solution, and the mixture was heated at 100° C. overnight in a sealed tube. The reaction mixture was cooled to room temperature and poured into water, and organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=9:1) to give the title compound (1.00 g, 97% yield).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([CH3:16])([CH3:15])[C:8](=[O:14])[NH:9]2)C=C.CN(C)[C:19]1[CH:24]=CC=C[CH:20]=1>>[CH2:24]([C:13]1[C:5]([OH:4])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:14])[C:7]2([CH3:15])[CH3:16])[CH:19]=[CH2:20]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cccc2c1C(C)(C)C(=O)N2
Product: C=CCc1ccc2c(c1O)C(C)(C)C(=O)N2
Temperature: 205 °C

Procedure:
914 mg (4.21 mmol) of 4-allyloxy-2,3-dihydro-3,3-dimethyl-1H-indol-2-one was added to 4 ml of N,N-dimethylaniline, and the mixture was heated for 30 hours at 205° C. while stirring. After the reaction, N,N-dimethylaniline was evaporated under reduced pressure. The residue was dissolved in chloroform, washed with water, 2N hydrochloric acid, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, chloroform:ethyl acetate=20:1), washed with ether-n-hexane, and filtered to obtain 890 mg (yield: 97.4%) of a brown oil of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](Cl)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22]([N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:16][CH3:17])[CH3:15])=[O:23]
Reactant: CNc1cnccc1-c1ccc(F)cc1OC
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine and 3-fluoro-5-(trifluoromethyl)benzoic acid chloride (CAS RN 171243-30-4). The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product-containing fractions were pooled and evaporated. The yellow solid was further purified by preparative HPLC (Phenomenex Gemini® column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (50:50 to 95:5). Light yellow solid (23%). MS (ESI): m/z=423.113 [M+H]+.
Reaction SMILES: C1(CC([NH:10][C@@H:11]2[C:46](=[O:47])[N:13]3[C:14]([C:30]([O:32][CH:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])=[C:15]([S:18][C:19]4[S:20][CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)[N:23]=4)[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(OC(C)C)(C)C>ClCCl.C(O)C(C)C>[NH2:10][C@@H:11]1[C:46](=[O:47])[N:13]2[C:14]([C:30]([O:32][CH:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:31])=[C:15]([S:18][C:19]3[S:20][CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[N:23]=3)[CH2:16][S:17][C@H:12]12
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3nc(-c4ccncc4)cs3)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(C)CO
Solvent: c1ccncc1
Solvent: CC(C)OC(C)C
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3nc(-c4ccncc4)cs3)CS[C@H]12

Procedure:
Benzhydryl 7β-phenylacetylamino-3-[4-(4-pyridyl)-2-thiazolylthio]-3-cephem-4-carboxylate (4.15 g, 6.0 mmol) was dissolved in dichloromethane (60 mL) and pyridine (0.726 mL, 9.0 mmol) and phosphorus pentachloride (1.87 g, 9.0 mmol) were successively added under ice-cooling. The mixture was stirred under ice-cooling for 1 hr. Isobutanol (8.0 mL) was added at once to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Isopropyl ether (300 mL) was added dropwise and the mixture was stirred for 10 min. The solvent was removed by decantation. The residual oil was suspended in ethyl acetate (600 mL) and saturated aqueous sodium hydrogencarbonate solution (200 mL) was added dropwise, after which the mixture was stirred for 15 min. The organic layer was separately taken, dried over magnesium sulfate and filtrated. The solvent was evaporated off under reduced pressure. Isopropyl ether (60 mL) was added to the residue, and the precipitated powder was collected by filtration, washed with isopropyl ether (20 mL) and dried under reduced pressure. yield: 3.18 g (95%)
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33])[O:16]2)[CH2:2][CH2:3]1
Reactant: CCCCC(=O)Cl
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.624 g, 2.1 mmoles), 4-dimethylaminopyridine (27 mg, 0.2 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (2.0 mL, 14 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 100 mL acetonitrile. Valeryl chloride (1.08 mL, 8.9 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 6 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in acetone and passed over a silica gel column (4.8×13 cm). After evaporation of the solvent, the product was further purified on a Chromatotron (4 mm silica gel plate) with a mixture of hexane:acetone (85:15). The product containing fractions were combined, concentrated, and loaded onto preparative silica gel plates (20×20×0.2 cm). The plates were developed in a mixture of chloroform-acetone (80:20). The product was scraped from the preparative plate and eluted from the silica gel with ethanol. The product was then flash chromatographed on a silica gel column (2.5×40 cm) with a mixture of chloroform:acetone (95:5). Lyophilization afforded 0.463 g of 6-(cyclopropylmethylamino)-9-((2R,5S)-5-((pentanoyloxy)methyl)-tetrahydro-2-furyl)-9H-purine as an oil (58% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.O[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cc(Br)ccc1OCCN1CCOCC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 67.3 %

Procedure:
A mixture of 4-bromo-2-fluorophenol (0.612 g, 3.2 mmol; described: in Finger et al. J. Amer. Chem. Soc. 1959, 81, 94), 4-(2-hydroxyethyl)morpholine (0.47 ml, 3.84 mmol) and triphenylphosphine (1.0 g, 3.84 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and cooled to 0° C. Diethyl azodicarboxylate (0.6 mL, 3.84 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 3.5 h. The solvent was evaporated and the residue partioned between water and methylene chloride. The organic phase was washed twice with a saturated sodium hydrogen carbonate solution, dried (MgSO4) and the solvent was evaporated. The product was purified by column chromatography on silica using a gradient of toluene/acetonitrile, (4:1 to 0:1), as the eluent to give 0.655 g (67% yield) of the title compound as a clear oil: 1H NMR (CDCl3) δ 7.21 (d, J=11 Hz, 1H), 7.16 (m, 1H), 6.83 (t, J=9 Hz, 1H), 4.14 (t, J=6 Hz, 3H), 3.71 (t, J=5 Hz, 4H), 2.80 (t, J=6 Hz, 2H), (t, J=5 Hz, 4H); 13C NMR (CDCl3, 100) δ 154.2, 151.7, 146.5, 146.4, 127.4, 127.4, 120.1, 119.9, 116.8, 116.8, 112.7, 112.7, 68.1, 67.1, 57.6, 54.3; MS (ESP) m/z 304, 306 (M++1).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](O)([CH2:14][CH:15]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:16]([F:19])([F:18])[F:17])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:26][C:24]1[CH:25]=[C:20]([CH:15]([C:16]([F:17])([F:19])[F:18])/[CH:14]=[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:7][CH:8]=2)\[CH3:13])[CH:21]=[C:22]([Cl:27])[CH:23]=1
Reactant: CC(O)(CC(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C/C(=C\C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
To a solution of 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5-trifluoropentan-2-ol (100 mg, 0.233 mmol) in toluene was added a catalytic amount of p-toluenesulfonic acid and the water was removed by azeotropic distillation over the course of 12 h. The reaction mixture was cooled to room temperature and dissolved in EtOAc. The solution was washed with sat aqueous NaHCO3 solution and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (30 mg, 31%).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Product: O=C(O[C@H]1CCNC1)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)acetic acid and t-butyl(3S)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:23][C:24]#[C:25][Si:26]([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[CH3:27][Si:26]([CH3:29])([CH3:28])[C:25]#[C:24][CH2:23][CH:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: C[Si](C)(C)C#CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCC(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an oven-dried 100-mL round-bottom flask was placed di(pyridin-3-yl)methane (0.100 g, 0.58 mmol) in dry THF (10 mL) under N2. The solution was cooled to 0° C. and LDA (0.580 mL of a 1.5 M solution, 0.87 mmol) was slowly added to form a dark red suspension. The suspension was stirred for 15 min at 0° C. and then 3-bromo-1-(trimethylsilyl)-1-propyne (0.164 mL, 1.16 mmol) was added via syringe. The reaction was warmed to rt, quenched with water (1 mL), and extracted with dichloromethane (2×25 mL). The organic layers were combined and dried over Na2SO4, filtered and concentrated to give the crude product 3-(4-(trimethylsilyl)-1-(pyridin-3-yl)but-3-ynyl)pyridine. This material was dissolved in methanol (5 mL), K2CO3 (0.500 g, 3.6 mmol) was added, and the mixture was stirred at rt for 48 h. The reaction was filtered and washed with dichloromethane (2×10 mL), then concentrated and dried. Purification by reverse phase chromatography gave 0.119 g (47%) of 3-(1-(pyridin-3-yl)but-3-ynyl)pyridine as a TFA salt. Analytical LCMS: single peak (214 nm), 0.416 min. ESIMS m/z 209.1 (C14H12N2+H+ requires 209.1079).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.FC1C=CC(Br)=CC=1.[Mg].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22](OC)[C:21]=1[C:29]1[O:30][CH2:31][C:32]([CH3:35])([CH3:34])[N:33]=1>C1COCC1>[Cl:19][C:20]1[C:21]([C:29]2[O:30][CH2:31][C:32]([CH3:35])([CH3:34])[N:33]=2)=[C:22]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: COc1cc(Cl)cc(Cl)c1C1=NC(C)(C)CO1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)COC(c2c(Cl)cc(Cl)cc2-c2ccc(F)cc2)=N1
Reaction time: 20 h
Yield: 85 %

Procedure:
4-Fluorophenylmagnesium bromide, prepared from 4-fluorobromobenzene (120 mmol) and magnesium (120 mmol), in dry THF (75 ml) was added dropwise to a stirred solution of 2-(2,4-dichloro-6-methoxyphenyl)-4,4-dimethyl-2-oxazoline (100 mmol) in dry THF (150 ml) under N2 at 20° C. Stirring of the solution was continued for 20 hours and then the reaction mixture was quenched by the addition of saturated ammonium chloride solution. The resulting mixture was extracted with ether (2×500 ml), dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (ethyl acetatehexane) to provide title compound (85%), mp 93°-95° C.
Reaction SMILES: [Si](O[C@H:9]([C@H]1CC(O)(C2C=CC=CC=2)CN1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:30])[NH2:29])[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14](F)C=1)(C(C)(C)C)(C)C.[Si]([O:58][C@H:59]([C@H:94]1[CH2:98][C@@H:97]([O:99][CH2:100][CH2:101][CH3:102])[CH2:96][N:95]1C(OC(C)(C)C)=O)[C@@H:60](NC(=O)C1C=C(C2OC=CN=2)C=C(C(N2CCC[C@@H]2COC)=O)C=1)[CH2:61][C:62]1[CH:67]=[C:66]([F:68])[CH:65]=[C:64]([F:69])[CH:63]=1)(C(C)(C)C)(C)C>Cl.O>[F:69][C:64]1[CH:63]=[C:62]([CH2:61][C@H:60]([NH:29][C:28](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([NH:20][CH:10]([C:11]3[CH:12]=[CH:17][C:16]([F:18])=[CH:15][CH:14]=3)[CH3:9])=[O:31])[CH:23]=2)[C@H:59]([OH:58])[C@H:94]2[CH2:98][C@@H:97]([O:99][CH2:100][CH2:101][CH3:102])[CH2:96][NH:95]2)[CH:67]=[C:66]([F:68])[CH:65]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1cc(F)cc(F)c1)NC(=O)c1cccc(C(N)=O)c1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: O
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)NC(C)c3ccc(F)cc3)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step 16 (B): N1-((1R,2 S)-3-(3,5-Difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propran-2-yl)-N3-(1-(4-fluorophenyl)ethyl)isophthalamide. The solution of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyoxy)-2-(3-(carbonyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (Step 16 (A), 38 mg) in HCl (4.0 M solution in dioxane, 1 mL) was added 2 drops of H2O and the mixture was stirred at rt for 1 h. The solvent was removed and the mixture was purified by reverse phase HPLC (30×100 mm PHENOMENEX-LUNA S5 column, 34-90% methanol/H2O/0.1% TFA) to give 30 mg of the title compound: 1H NMR (CD3OD, 500 MHz) δ ppm 0.97 (3H, m), 1.58 (3H, d, J=5 Hz), 1.62 (2H, m), 2.17 (1H, m), 2.50 (1H, m), 2.86 (1H, m), 3.34-3.49 (5H, m), 3.81 (1H, m), 4.06 (1H, dd, J=5, 10 Hz), 4.22-4.25 (2H, m), 5.21-5.27 (1H, m), 6.73 (1H, m), 6.89-6.90 (2H, m), 7.07 (2H, m), 7.41-7.44 (2H, m), 7.53 (1H, t, J=10 Hz), 7.79-7.82 (1H, m), 7.96 (1H, m), 8.12-8.14 (1H, m), MS (ESI) (M+H)+ 584.32.
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.[CH:16]1([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=2)[CH2:18][CH2:17]1.[OH-].[K+]>CN1C(=O)CCC1>[CH:16]1([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH2:26][N:6]3[C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=4[C:4]4[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]3=4)=[CH:23][CH:24]=2)[CH2:18][CH2:17]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(C2CC2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C3CC3)nc2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-cyclopropyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:17][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)NC(C)c1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(C)c1ccc(CCl)cc1

Procedure:
A solution of N-(1-(4-formylphenyl)ethyl)acetamide (0.32 g) and sodium borohydride (63 mg) in ethanol (10 ml) was stirred at room temperature for 1 hr. Thereto was added 2N hydrochloric acid (1 ml) to stop the reaction, and the reaction mixture was poured into ice water (100 ml) and extracted with ethyl acetate. The extract was washed successively with saturated sodium hydrogencarbonate solution (500 ml) and saturated brine (500 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=2:5, later 1:4) to give N-(1-(4-hydroxymethylphenyl)ethyl)acetamide (100 mg) as a colorless oil. A solution of the obtained N-(1-(4-hydroxymethylphenyl)ethyl)acetamide (100 mg) and thionyl chloride (0.050 ml) in chloroform (5 ml) was stirred at 60° C. for 1 hr. This was diluted with ethyl acetate (100 ml) and poured into a saturated sodium hydrogencarbonate solution (100 ml) to separate the organic layer. The aqueous layer was extracted with ethyl acetate (100 ml) and combined with the organic layer obtained earlier. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate alone) to give N-(1-(4-chloromethylphenyl)ethyl)acetamide (92 mg) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:16]=1[C:17](=[S:20])[NH:18][NH2:19]>CCO.C(Cl)Cl>[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:16]=1[C:17]1[S:20][C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:19][N:18]=1
Reactant: NNC(=S)c1cc(F)ccc1F
Reactant: COCOCC(=O)c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: COCOCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of 2-(methoxymethoxy)-1-phenylethanone (0.60 g, 3.33 mmol) in EtOH/DCM (3:1, 12 mL) was added 2,5-difluorobenzothiohydrazide (0.63 g, 3.33 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure. The brown residue was chromatographed (9:1 hexanes/ethyl acetate) to provide the product as a yellow oil (0.73 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([O:10][C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: COCCOc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCCOc1ccc(C(=O)Oc2cc(F)c(F)c(F)c2)cc1
Reaction time: 8 h

Procedure:
A solution of 3,4,5-trifluorophenol (0.38 g, 2.55×10−3 mol) in dichloromethane (10 cm3) was added to a solution of N,N-dicyclohexylcarbodiimide (0.63 g, 3.06×10−3 mol), 4-(2-methoxyethoxy)benzoic acid (0.50 g, 2.55×10−3 mol), 4-(dimethylamino)pyridine (0.03 g 2.55×10−4mol) in dichloromethane (5 cm3), at 0° C. and then left to stirred overnight, filtered to remove precipitated material (DCU) and the filtrate evaporated down under reduced pressure. The crude product was purified by column chromatography on silica gel using a 1:1 dichloromethane-petroleum ether (40°-60° C.) mixture as eluent, followed by recrystalisation from ethanol. Yield 0.32 g (38%), GC purity (99.76%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]CC)=[O:16])[CH:13]=2)[N:8]=[C:7]([CH3:20])[C:6]1=[O:21].[OH-].[Na+].CO.Cl>O>[C:15]([C:12]1[CH:13]=[C:14]2[C:9]([N:8]=[C:7]([CH3:20])[C:6](=[O:21])[N:5]2[CH2:4][C:3]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:2]=2[Cl:1])=[CH:10][CH:11]=1)([OH:17])=[O:16]
Reactant: CCOC(=O)c1ccc2nc(C)c(=O)n(Cc3ccc(Cl)cc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2ccc(C(=O)O)cc2n(Cc2ccc(Cl)cc2Cl)c1=O
Yield: 77.6 %

Procedure:
1-(2,4-Dichlorobenzyl)-7-(ethoxycarbonyl)-3-methyl-2(1H)-quinoxalinone (0.50 g) in a mixture of a 5% aqueous sodium hydroxide solution (3 g) and methanol (20 ml) was heated under reflux for 1 hr. After cooling, concentrated hydrochloric acid (4 ml) and water (10 ml) were added to the reaction mixture and the precipitate was collected by filtration. The precipitate was washed with water (30 g) and dried to give the object compound (0.36 g) as yellow crystals.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].COC1C=CC(N=[C:18]([C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=CC=1.S(S([O-])=O)([O-])=O>C(O)(=O)C.O>[CH3:29][N:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(=Nc1ccc(OC)cc1)c1cccn1C
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1cccn1C
Reaction time: 0.17 h

Procedure:
Three equivalents of sodium dithionite (0.36 g) is added in one portion with vigorous stirring to a solution of 0.2 g ethyl α-(4-methoxyphenylimino)-1-methylpyrrole-2-acetate in 6 ml glacial acetic acid plus 2.5 ml water. After ten minutes two additional equivalents of dithionite is added. After 10 mins more, a sufficient sample for G.C. analysis is poured into ice and extracted with chloroform. Analysis by gas chromatography (G.C.) with an internal standard measures 34% ethyl 1-methylpyrrole-2-acetate.