Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:19]=[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18].C(O)(C)C.[NH4+]=S>O>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:2]=2[Cl:1])=[C:10]([F:18])[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 103.2 %

Procedure:
The following materials were added to a 2-L Chem-Glass reactor: 3-chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine (110.00 g, 221 mmol), isopropyl alcohol (990.00 mL), and ammonium sulfide (˜40% in water, 297.00 mL, 2324 mmol). The mixture was allowed to stir at 20° C. for 3-4 h. 3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine was not detected by HPLC analysis. The reaction mixture was heated to 70° C. and allowed to stir for 3-4 h. Once the reaction was complete, water (14 mL/g·LR) was added. The reaction mixture was cooled to 20° C. (reaction temp) over 1 h. Upon cooling a solid precipitated and was filtered off and washed with water (12.5 mL/g·LR), followed by heptane:MTBE (4:1; 5 mL/g·LR). After LOD (˜25%), 95.3 g of crude 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine (90AP) was obtained. The crude 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine was dissolved into n-BuOAc (7 mL/g·LR) by heating to approximately 85° C. At 85° C., heptane (7 mL/g·LR) was added dropwise until the solution became cloudy. The solution was then allowed to cool to 20° C. with stirring. Once at 20° C., the slurry was aged for 8 h. The solid was filtered, washed with heptane (5 mL/g·LR), and then dried overnight in a vacuum oven at 60° C. to afford 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine (62.53 g; 67.69% yield) as a faint yellow solid. 1H NMR (CDCl3) δ 6.23 (dd, 1H, J=1.0, 5.6 Hz), 6.43 (m, 1H), 6.49 (dd, 1H, J=2.5, 12.1 Hz), 6.92 (t, 1H, J=8.6 Hz), 7.25-7.60 (m, 8H), 7.87 (m, 2H), 7.95 (d, 1H, J=6.1 Hz); MS (ESI+) m/z 418.6 (M+H)+.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])([CH:12]2[CH2:17][CH2:16][C:15](=COC)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:29]([OH:31])=O.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([CH:6]1[CH2:7][CH2:8][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])([C:12]2([CH:29]=[O:31])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=CO
Reactant: CCCCCC1CCC(c2cccc(F)c2F)(C2CCC(=COC)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(c2cccc(F)c2F)(C2(C=O)CCCCC2)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The compound (39) (8.1 g), formic acid (87%; 9.5 g) and toluene (100 ml) were mixed, and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to 30° C., and then water (100 ml) and toluene (200 ml) were added thereto and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, giving a white solid. This residue was dissolved in toluene (50 ml). The solution was added to a mixture of sodium hydroxide (95%; 0.5 g) and Solmix A-11 (32 ml) which had been cooled to 7° C., and the solution obtained was stirred at 10° C. for 2 hours. Then, an aqueous 2N-sodium hydroxide solution (16 ml) was added thereto, and the mixture was stirred at 5° C. for 2 hours. The reaction mixture obtained was poured into a mixture of water (200 ml) and toluene (200 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue obtained was concentrated, purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder and dried, giving 7.5 g of 1-[4-pentyl-(2,3-difluorophenyl)cyclohexyl]-cyclohexanecarboaldehyde (40). The yield based on the compound (39) was 97.1%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[C:17]([C:21]([OH:23])=[O:22])([F:20])([F:19])[F:18]>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:21]([OH:23])=[O:22].[F:1][C:2]([F:16])([F:15])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(F)(F)F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)C1CCNC1

Procedure:
tert-Butyl 3-(trifluoromethyl)pyrrolidine-1-carboxylate (100 mg, 0.42 mmol) was treated with 20% CF3CO2H in CH2Cl2 at room temperature overnight. The volatiles were removed in vacuo to give the subtitled compound (106 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].C(N(CC)CC)C.[CH2:25]([NH:27][C:28]([CH:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31])=[O:29])[CH3:26]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:35]1[CH2:34][CH2:33][N:32]([CH:30]([C:28]([NH:27][CH2:25][CH3:26])=[O:29])[CH3:31])[CH2:37][CH2:36]1)=[O:9]
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Reactant: CCNC(=O)C(C)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCNC(=O)C(C)N1CCN(C(=O)C=Cc2cc(OC)c(OC)c(OC)c2)CC1
Reaction time: 1 h

Procedure:
17.19 g of 3,4,5-trimethoxycinnamoyl chloride and 6.78 g of triethylamine are added with ice cooling to a solution of 9.54 g of 1-[1-(ethylaminocarbonyl)ethyl]piperazine in 200 ml of chloroform, and the resulting solution is kept standing at room temperature for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=2[F:29])[N:17]=1.[C:30]([CH:32]1[CH2:34][CH2:33]1)#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([C:31]#[C:30][CH:32]3[CH2:34][CH2:33]3)=[CH:24][C:23]=2[F:29])[N:17]=1
Reactant: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(I)cc3F)c(=O)[nH]2)c1)C(F)(F)F
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C#CC4CC4)cc3F)c(=O)[nH]2)c1)C(F)(F)F
Yield: 43.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 by using N-(4-chloro-3-(1-(2-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (Intermediate-126, 1.100 g, 3.88 mmol), ethynylcyclopropane (0.127 g, 1.93 mmol), TBAF (1.10 g, 3.88 mmol), bis(triphenylphosphine)palladium(II) chloride (0.036 g, 0.051 mmol) and DMSO (3.0 mL) to afford 0.400 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 0.95 (m, 4H), 1.56 (m, 1H), 4.44 (br s, 2H), 7.32 (d, J=7.8 Hz, 1H), 7.42-7.46 (m, 2H), 7.58 (t, J=7.8 Hz, 1H), 7.65 (m, 3H), 10.12 (br s, 1H); MS (m/z): 479.11 (M+H)+.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:38][NH:39][CH2:40][CH3:41].Cl.O>>[CH2:40]([N:39]([CH3:38])[CH2:26][CH2:25][CH2:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12])[CH3:41]
Reactant: CCNC
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Agent: Cl
Solvent: O
Product: CCN(C)CCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 25 °C

Procedure:
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) and methyethylamine (0.45-0.75 mmol) was stirred at 90° C. for about 2 hours in a sealed tube. After cooling to ambient temperature the reaction mixture was solvent evaporated. It was dissolved in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in methanol, and ethereal hydrochloride was added. The mixture was then concentrated and dried for 29 hours at 80° C. in vacuo. Ethyl-methyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine hydrochloride was a tan semi-solid (53.2 mg, 77.1%); Mass Spectrum (+EI, [M+H]+) m/z 424. 1HNMR (500 MHz, DMSO-d6): δ14.14-14.17 (br, 1H), 9.71-9.77 (br, 1H), 8.74-8.76 (m, 1H), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.03-8.05 (m, 1H), 7.70-7.74 (m, 1H), 7.56-7.64 (m, 3H), 7.29 (d, 1H, J=2.19 Hz), 7.08-7.10 (m, 1H), 4.08-4.11 (m, 2H), 3.04-3.25 (m, 2H), 2.72 (s, 3H), 1.18-1.21 ppm (m, 3H). Elemental Analysis for C23H25N3O3S. 1.00 mol HCl.0.90 mol H2O: Calcd: C, 58.01; H, 5.88; N, 8.82; Found: C, 58.37; H, 5.55; N, 8.50.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:8]([OH:10])=[O:9])[N:6]=1.[C:17](OC(=O)C)(=[O:19])C>C(O)=O>[CH:17]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:19]
Reactant: CC(C)CON=C(C(=O)O)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(C)CON=C(C(=O)O)c1csc(NC=O)n1
Yield: 86.9 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-iso-butoxyiminoacetic acid (syn isomer, 11.5 g.), acetic anhydride (19.3 g.) and formic acid (8.7 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-iso-butoxyiminoacetic acid (syn isomer, 11.15 g.), mp 163° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2SC)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]([NH:21][C:22]([NH:24][C:25]([CH2:27][CH3:28])=[O:26])=[NH:23])([CH3:20])[CH3:19]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[NH:11][C:10]2=[N:23][C:22]([NH:21][CH:18]([CH3:19])[CH3:20])=[N:24][C:25]([CH2:27][CH3:28])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CSC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Reactant: CCC(=O)NC(=N)NC(C)C
Solvent: ClC(Cl)Cl
Product: CCC(=O)N=C(N=C1NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1)NC(C)C
Temperature: 50 °C
Yield: 24.2 %

Procedure:
Adapted the alternative method for the preparation of 4d as follows: To the solution of the crude dione 15 (0.413 g, 1.429 mmol) in 50 ml of dry CHCl3 was added N-isopropyl-N′-(ethylcarbonyl)guanidine (0.206 g, 1.191 mmol). The reaction mixture was heated at 50° C. for 48 hours. The reaction was quenched with water, extracted with chloroform and dried over Na2SO4. The solvent was removed in vacuo and the crude product was purified with a silica gel column using 3% EtOAc/CHCl3 as eluent to yield 4a as a white solid (0.115 g, 20%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.CCO>O>[NH2:6][C:5]1[C:4]([N+:12]([O-:14])=[O:13])=[CH:3][C:2]([F:1])=[CH:8][C:7]=1[NH2:9]
Reactant: Nc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: Nc1cc(F)cc([N+](=O)[O-])c1N
Yield: 50 %

Procedure:
A solution of 4-fluoro-2,6dinitroaniline (125 mg, 0.62 mmole) in freshly prepared 6% (NH4)2S (5 mL) and EtOH (5 mL) was refluxed for 30 min, diluted with water (10 mL) and kept at 4° C. for several hours. The precipitate was collected and washed with cold water (2×1 mL), affording 53 mg (50%) of 1,2-diamino-4-fluoro-6-nitrobenzene as red crystals. 1H NMR (CDCl3 : δ 3.619 (s, 2H), 5.724 (s, 2H), 6.732 (dd, 1H, J1 =2.4 Hz, J2 =8.4 Hz), 7.403 (dd, 1H, J1 =2.4 Hz, J2 =8.4 Hz).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.CN(C)[CH:23]=[O:24]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:23]=[O:24]
Reactant: Fc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)cccc1Br
Temperature: -69 °C
Reaction time: 1.5 h
Yield: 96.3 %

Procedure:
A solution of n-butyllithium (2.5M in hexanes, 2.866 L, 7.17 mol) is added dropwise to a stirred solution of diisopropylamine (745.7 g, 7.37 mol) in tetrahydrofuran (1.630 L) such that the temperature is maintained in the range −60 to −78° C. The resulting suspension is stirred for 1.5 h at −75 to −78° C. A solution of 1-bromo-3-fluorobenzene (1.228 Kg, 7.02 mol) in tetrahydrofuran (2.40 L) is added slowly to the reaction mixture over 1.5 h. Stirring is continued for 30 min at −70 to −71° C. Dimethylformamide (511.3 g) is added over 1 h. The reaction mixture is allowed to warm to −15° C. and is quenched by the slow addition of acetic acid (1.965 L) over 20 min. TBME (5.20 L) and water (6.25 L) are added. The resultant solution is stirred vigorously and the layers are separated. The aqueous layer is extracted with TBME (1.965 L) twice and the combined organic layers are washed with 0.2 M hydrochloric acid (2×5.00 L), saturated aqueous sodium hydrogen carbonate solution (2×2.50 L) and water (3.50 L). The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow crystalline solid (1.367 Kg, 96%). 1H NMR (CDCl3): δ 10.36 (s, 1H), 7.49 (d, 1H, 3=7.8 Hz), 7.45-7.37 (m, 1H), 7.15 (t, 1H, J=7.9 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36](O)=[O:37])[CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:28]4[CH:27]=[N:26][C:35]5[C:30]([CH:29]=4)=[CH:31][CH:32]=[CH:33][CH:34]=5)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cnc5ccccc5c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoline-3-carboxylic acid as starting compounds.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1ccc(F)c(C(=O)O)c1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(F)ccc(C)c1F
Temperature: 25 °C
Yield: 86 %

Procedure:
To a 0° C. solution of 2,6-difluoro-3-methylbenzoic acid (10.0 g, 58.1 mmol, 1.0 equiv) in dry methanol (100 mL) was added dropwise thionyl chloride (4.64 mL, 63.9 mmol, 1.1 equiv). The resulting solution was refluxed overnight. After the reaction mixture was allowed to cool to room temperature, the solvent was removed in vacuo. The product was dissolved in ethyl acetate and washed with aq. satd. NaHCO3. The EtOAc layer was dried over sodium sulfate, filtered and concentrated in vacuo to provide the desired ester (9.35 g, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH2:27])[CH:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[NH:12][CH:11]=1)[CH2:7][O:8][CH3:9])[CH3:2].[CH2:29]=O.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:5]1[CH:6]([CH2:7][O:8][CH3:9])[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[NH:12][C:11]=2[CH2:29][NH:27]1)=[O:28])[CH3:2]
Reactant: CCOC(=O)C(N)C(COC)c1c[nH]c2cccc(Cc3ccccc3Cl)c12
Reactant: C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1NCc2[nH]c3cccc(Cc4ccccc4Cl)c3c2C1COC
Yield: 18.6 %

Procedure:
5.2 g (0.013 mol) of 2-amino-3-[4-(2-chlorobenzyl)-indol-3-yl]-4-methoxybutyric acid ethyl ester is refluxed for one hour with 0.44 g of paraformaldehyde in 500 ml of toluene under argon on a water separator. Then it is filtered off from a turbidity. The evaporation residue is chromatographed on silica gel with equal parts of acetone and dichloromethane and yields 1 g (19% of theory) of 1,2,3,4-tetrahydro-5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH3:17])=[CH:4][CH:3]=1.[ClH:19].Cl.[NH2:21][CH2:22][CH2:23][O:24][NH2:25].N1C=CC=CC=1>C(O)C>[ClH:19].[ClH:19].[NH2:21][CH2:22][CH2:23][O:24][N:25]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH3:17]
Reactant: NCCON
Reactant: Cc1nccn1CCCC(=O)c1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1nccn1CCCC(=NOCCN)c1ccc(F)cc1
Reaction time: 3 h
Yield: 116 %

Procedure:
A mixture of 1-(4-fluorophenyl)-4-(2-methyl-1-(1H)-imidazolyl)-1-butanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.18 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol/ether to give 3.2 g (70%) of product, mp 219°-221° C. (dec).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[F:12][C:13]([F:36])([F:35])[C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[N:20]=[CH:19][CH:18]=1)=[O:15]>C(O)(=O)C>[N+:8]([C:18]1[CH:19]=[N:20][N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[C:17]=1[NH:16][C:14](=[O:15])[C:13]([F:36])([F:35])[F:12])([O-:11])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=C(Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(F)(F)F
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(F)(F)F
Reaction time: 20 h
Yield: 77.6 %

Procedure:
2.4 ml (0.0258 mol) of acetic anhydride and 1.1 ml (0.025 mol) of 98% strength nitric acid are added in succession to 10 g (0.0235 mol) of 5-trifluoroacetamido-1-(2,3,6-trichloro-4-trifluoromethylphenyl)-pyrazole in 20 ml of glacial acetic acid at room temperature. After the mixture has been stirred for 20 hours, it is concentrated in vacuo, the residue is taken up in 100 ml of methylene chloride and the mixture is extracted with 400 ml of 5% strength aqueous sodium carbonate solution. The aqueous phase is acidified and extracted with 200 ml of methylene chloride. The combined organic phases are dried over magnesium sulphate and freed from the solvent in vacuo. 8.6 g (77.6% of theory) of 4-nitro-5-trifluoroacetamido-1-(2,3,6-trichloro-4-trifluoromethylphenyl)-pyrazole of melting point 136° C.-137° C. are obtained.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[CH:10][CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:17]1([CH3:20])[C:16]([CH3:21])([CH3:22])[O:15][B:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:9][CH:10]=2)[O:18]1
Reactant: CC1(C)OB(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Reactant: Brc1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(-c3ncccn3)cc2)OC1(C)C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
A degassed solution of 2-bromopyrimidine (1.5 g, 9.4 mmol), 2,2′-(1,4-phenylene)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (5.1 g, 16.0 mmol), 1.0 M aq K3PO4 (28.3 mL, 28.3 mmol), and Pd(PPh3)4 (330 mg, 0.31 mmol) in DMF (140 mL) was heated to 80° C. and stirred at this temperature for 16 h. Water (100 mL) was added to the reaction mixture and was extracted with EtOAc (3×200 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified via flash chromatography using an eluent of 17% EtOAc in n-heptane to afford the title compound as a white solid (0.7 g, 28%). MS (LCMS) m/z 283.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 12H) 7.19 (t, J=4.68 Hz, 1H) 7.93 (d, J=8.00 Hz, 2H) 8.43 (d, J=7.81 Hz, 2H) 8.81 (d, J=4.68 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH3:20])(=[O:4])[CH2:2][CH3:3].[CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])([CH3:23])[CH3:22]>C(#N)C>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[CH:21]([CH3:23])[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH3:20])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Reactant: CC(C)c1ccccc1N
Solvent: CC#N
Product: CCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C(C)C
Yield: 8 %

Procedure:
A mixture of 3-propanoyl-4-chloro-8-(2-methylthioethoxy)quinoline (305 mg, 1 mmol) and 2-isopropylaniline (1 ml) in 25 ml acetonitrile was refluxed overnight. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. The residue was chromatographed on a prep-TLC (methylene chloride:ethyl acetate 1:1) yielding 30 mg (8%) of the desired product.