Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH3:20][N:21]([CH:23]=[O:24])[CH3:22]>>[Cl:1][C:2]1[C:3]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:4]([CH2:8][O:9][C:23](=[O:24])[N:21]([CH3:22])[CH3:20])[CH:5]=[N:6][CH:7]=1
Reactant: OCc1cncc(Cl)c1COC1CCCCO1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CN(C)C(=O)OCc1cncc(Cl)c1COC1CCCCO1
Reaction time: 8 h

Procedure:
To a solution of [5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridin-3-yl]-methanol (0.11 g, 0.43 mmol) and NaH (17 mg, 0.86 mmol) in DMF (3 mL) dimethylcarbamyl chloride (0.39 μL, 2.15 mmol) was added and stirring was continued at RT overnight. Solvents were concentrated in vacuo and the residue was partitioned between EA (10 mL) and saturated NaCl solution (10 mL). After extraction of the aqueous layer with EA (2×10 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 328.9 [M+H+].
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[O:11]=[C:7]1[NH:6][C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[N:4][C:3]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:8]1[C:9]#[N:10]
Reactant: C1CCNC1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: N#Cc1c(N2CCCC2)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 270 mg (3.80 mmol) of pyrrolidine to give 64 mg (59% of theory) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][N:8]([CH2:10][CH2:11][OH:12])[CH2:7][N:6]([CH2:13][CH2:14][OH:15])[CH2:5]1.[OH-].[K+].[C:18](OC)(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(O)(=O)CCCCCCC/C=C\CCCCCCCC>CO.C(Cl)Cl>[C:18]([O:12][CH2:11][CH2:10][N:8]1[CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][N:6]([CH2:13][CH2:14][OH:15])[CH2:7]1)(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: OCCN1CN(CCO)CN(CCO)C1
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN1CN(CCO)CN(CCO)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 20 g of 1,3,5-tris-hydroxyethyl perhydro-s-triazine from the method of Paquin, Ber., 82, 316 (1949) and 0.30 g (5.8 mole percent) of powdered KOH is heated at 80° C. under reduced pressure (less than 0.1 mm) for 6 hours. Methyl oleate (30g ) from acid-catalyzed esterification of oleic acid in methanol is then added and the resulting mixture (in two phases) is stirred at 80° C. under the reduced pressure overnight. The homogeneous material which is obtained is dissolved in CH2Cl2, washed with water, dried over potassium carbonate, then is concentrated into a light yellow oil of 41 g (84.9 percent of theory). Both the infrared (1745 cm-1) and nuclear magnetic resonance spectra are consistent with the desired 1,3,5-triazine-1,3,5-(2H,4H,6H)triethanol monooleate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[Br:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[C:3]=1[C:30]#[N:31].P(O)(O)[OH:33]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[Br:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[C:3]=1[C:30]([NH2:31])=[O:33]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2Br)c1N
Reactant: OP(O)O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2Br)c1N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 5-amino-1-(2-bromo-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (137 mg, 0.287 mmol) in phosphorous acid (85 wt. % in H2O, 10 mL) was stirred at 100° C. for 1 hr, until TLC and LCMS analysis showed that most of starting material was consumed. The reaction was cooled to room temperature and partitioned between water (40 mL) and EA (40 mL). Organic layer was separated from aqueous layer. The aqueous phase was then extracted with EA (20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated to get the crude product (149 mg) which was used in next step without further purification. MS (ESI) m/e [M+1]+494, 496.
Reaction SMILES: CN(C(N[C@H](C(O)=O)C(C)C)=[O:13])CC1N=C(C(C)C)SC=1.[NH2:22][C@@H:23]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:24][C@H:25](O)[C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C1COCC1>[NH2:22][C@H:23]([C@@H:24]([OH:13])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][CH2:38][C:39]1[S:43][CH:42]=[N:41][CH:40]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 126.3 %

Procedure:
A solution of 70 mg (0.223 mmol) of N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine, 79 mg (0.186 mmol) of (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane, 30 mg (0.223 mmol) of 1-hydroxybenzotriazole hydrate, and 51 mg (0.266 mmol) of N-ethyl-N'-dimethylaminopropyl carbodiimide in 2 ml of THF was stirred at ambient temperature for 16 h. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using 97:3 CH2Cl2 :CH3OH to provide 100 mg (74%) of the desired compound (Rf 0.4, 95:5 CH2Cl2 :CH3OH) as a solid. 1H NMR (d6 -DMSO) δ0.73 (d, J=7 Hz, 6H), 1.30 (d, J=7 Hz, 6H), 1.45 (m, 2H), 1.87 (m, 1H), 2.5-2.7 (m, 4H), 2.87 (s, 3H), 3.23 (heptet, J=7 Hz, 1H), 3.57 (m, 1H), 3.81 (m, 1H), 3.93 (m, 1H), 4.15 (m, 1H), 4.44 (AA', 2H), 4.62 (d, J=6 Hz, 1H), 5.13 (AA', 2H), 6.01 (d, J=9 Hz, 1H), 6.89 (d, J=9 Hz, 1H), 7.1-7.2 (m, 11H), 7.68 (d, J=9 Hz, 1H), 7.85 (s, 1H), 9.05 (s, 1H). Mass spectrum: (M+H)+ =721.Anal. Calcd for C37H48N6O5S2.0.5H2O: C, 60.88; H, 6.77; N, 11.51.Found: C, 60.68; H, 6.53; N, 11.36.
Reaction SMILES: Br.[NH2:2][CH:3]([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+].O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:2][CH:3]([CH3:12])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CC(N)Cc1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(Cc1ccc(O)cc1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A mixture of 2.32 g of 4-(2-aminopropyl)phenol hydrobromide, 4.2 g of sodium bicarbonate, 50 ml of water, 100 ml of ethyl acetate and 2.11 g of 4-chlorophenylsulfonyl chloride is stirred at room temperature for 3 hours. After the reaction, the ethyl acetate layer is separated therefrom, dried and evaporated to remove the solvent. 3.25 g of 4-[2-(4-chlorophenyl)sulfonylaminopropyl)phenol are obtained as brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=3)[N:17]=2)[CH:9]=[N:8]1.C(O)(=O)C.[NH:33]1[CH2:36][CH:35]([C:37]([OH:39])=[O:38])[CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:25][N:33]4[CH2:36][CH:35]([C:37]([OH:39])=[O:38])[CH2:34]4)=[CH:27][CH:28]=3)[N:17]=2)[CH:9]=[N:8]1
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1ccc(-c2noc(-c3cnn(-c4ccccn4)c3C(F)(F)F)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4cnn(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 63.5 %

Procedure:
To a solution of 4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (1.0 g, 2.60 mmol) in DCM (10 mL) was added acetic acid (15 mL) and azetidine-3-carboxylic acid (1.5 eq, 3.90 mmol). The mixture was stirred at RT for 40 min., then a suspension of sodium triacetoxyborohydride (1 eq, 2.60 mmol) in DCM (30 mL) was added dropwise over 1.5 h. The volatiles were removed in vacuo, water (200 mL) was added and the resulting solid was collected by filtration. Ethyl acetate (40 mL) was added to the crude product and after sonication for 30 min, the solids were collected by filtration and washed additional ethyl acetate to afford 1-(4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzyl) azetidine-3-carboxylic acid (777 mg, 1.65 mmol) as a white solid. The compound had an HPLC retention time=2.55 min. Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. LC/MS M+1=471.05. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.21-3.25 (m, 3H), 3.40-3.44 (m, 2H), 3.64 (s, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.69 (ddd, J=0.8 Hz, 4.7 Hz, 8.3 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 8.03 (d, J=8.3 Hz, 2H), 8.20 (dt, J=1.9 Hz, 7.7 Hz, 1H), 8.66 (dd, J=1.1 Hz, 4.1 Hz, 1 H) 8.73 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31].Cl>>[CH3:29][S:30]([C:33]1[CH:34]=[C:35]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:28])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:36]=[CH:37][CH:38]=1)(=[O:31])=[O:32]
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(C)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 555.3 [(M+H)+]; mp 211° C.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21])([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([C:11]([OH:12])([C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=1)[CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])=[O:21])([O-:16])=[O:15]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: OCCOCCOCCOCCO
Product: O=C(c1cccc([N+](=O)[O-])c1)C(O)(COCCOCCOCCO)C(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Tetraethylene glycol (58.2 g, 0.3 mole) was treated with m-nitrobenzoyl chloride, following the general procedure described in Example 1, Part A. After the usual work-up, the product was crystallized from ethyl acetate/hexanes at -20° C. for 3 days to give bis-(3-nitrobenzoyl)-tetraethylene glycol (110 g) as a pale yellow solid, m.p. 38°-40° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CO>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#Cc1c(F)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound, 2-Bromo-6-fluorobenzonitrile, the procedure for the preparation of which may be found in Hynes, John B. et. al., J. Hetercycl. Chem. 1988, 25, 1173-7, (2.0 g, 10.0 mmol) and phenylboronic acid (3.66 g, 30 mmol) were added to a mixture of toluene (80 mL), methanol (20 mL), and 2 M aqueous sodium carbonate (20 mL). This mixture was refluxed while stirring under argon for 15 min. The resulting mixture was cooled to room temperature and tetrakis(triphenylphosphine)palladium(0) (1.16 g, 1 mmol) was added. The. resulting mixture was then refluxed for 12 hours while stirring under argon. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water (2×), brine (1×), dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0-10% methylene chloride in hexane. Recrystallization from methylene chloride hexane gave the title product as a white crystalline solid. mp 78-79° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:22][C:21]=1[OH:32])=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C>[CH2:38]([O:37][C:35]([CH2:34][O:32][C:21]1[CH:22]=[C:23]([O:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][C:20]=1[C:18](=[O:19])[CH:17]=[CH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:36])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: CCCCCCCc1ccccc1C=CC(=O)c1ccc(OCC=C(C)C)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCc1ccccc1C=CC(=O)c1ccc(OCC=C(C)C)cc1OCC(=O)OCC
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To a suspension of 310 mg of 60% oily sodium hydride in 10 ml of dry DMF was added dropwise a solution of 2.8 g of 2-n-heptyl-2'-hydroxy-4'-(3-methyl-2-butenyloxy)chalcone in 10 ml of DMF with ice cooling. Then, 1.2 g of ethyl bromoacetate was added, and the mixture was stirred at room temperature for an hour. After neutralization with dilute hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel column with n-hexane containing 1% ethyl acetate to give 1.83 g of 2'-ethoxycarbonylmethoxy-2-n-heptyl-4'-(3-methyl-2-butenyloxy)-chalcone. To a solution of this compound in 30 ml of ethanol was added 15 ml of 10% aqueous potassium carbonate solution, and the mixture was stirred at 60° C. for 4.5 hours. After neutralization with dilute hydrochloric acid with ice cooling, the precipitated solid was collected by filtration and recrystallized from ethanol to give 1.23 g of 2'-carboxymethoxy-2-n-heptyl-4'-(3-methyl-2-butenyloxy)chalcone as pale yellow plates.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[Mg]Cl.[O:11]=[C:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl-].[Mg+2].[Cl-]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:12]1([OH:11])[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: Fc1ccc(F)c([Mg]Cl)c1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1(O)c1cc(F)ccc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In step 6A-1, (2,5-difluorophenyl)magnesium chloride (6-1) was added drop-wise to a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (6-2) (9.6 g, 52 mmol) in THF under argon at −78° C. A maximum of 5 mL aliquots was used to minimize the temperature increase of the magnesium chloride reagent. The resulting solution was then stirred at −78° C. for one hour. The solution was then warmed to room temperature and quenched with concentrated HCl (4 mL). The solvent was then removed using a rotary evaporator resulting in a light yellow residue. The residue was then reconstituted in ethyl acetate and extracted with brine (3×150 mL). The organic layer was then dried using sodium sulfate. The ethyl acetate was removed yielding tert-butyl 2-(2,5-difluorophenyl)-2-hydroxypyrrolidine-1-carboxylate (6-3) as a light yellow oil. m/z=300 [M+1] The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:14]([CH:15]=[O:16])[CH:13]=2)[CH:3]=1
Reactant: O=Cc1cccc(O)c1
Reactant: N#Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Yield: 91.7 %

Procedure:
4-Chloro-2-fluorobenzonitrile (1.00 g, 6.43 mmol), 3-hydroxybenzaldehyde (0.79 g, 6.43 mmol) and cesium carbonate (2.09 g, 6.43 mmol) were heated with stirring in dry DMF (5 ml) at 50° C. for 23 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (3×), 10% aqueous sodium carbonate (2×), water, brine, and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-formyl-phenoxy)-benzonitrile (1.52 g, 91%) as a yellow oil which solidified.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N+:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])#[C-:15]>>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]1[O:6][CH:15]=[N:14][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: [C-]#[N+]CC(=O)OC
Product: COC(=O)c1ncoc1-c1ccc([N+](=O)[O-])cc1Cl

Procedure:
The procedures of Example 1-(l) were followed, except for replacing the 2-methoxy-4-nitrobenzoic acid with 18.1 g (0.09 g) of 2-chloro-4-nitrobenzoic acid and replacing the ethyl isocyanoacetate with 9.9 g (0.1 mol) of methyl isocyanoacetate, to give 16.2 g (0.057 mol, 63.7% based on the 2-chloro-4-nitrobenzoic acid) of the title compound.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[CH3:24][S:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[CH3:24][S:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:31][CH:30]=1)(=[O:27])=[O:26]
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Product: CC/C(Nc1ccc(NS(C)(=O)=O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and N-methylsulphonyl-p-phenylenediamine
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]=5[NH2:25])[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]=5[NH:25][S:28]([CH3:27])(=[O:30])=[O:29])[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(N)c45)[nH]c3c2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(NS(C)(=O)=O)c45)[nH]c3c2)CC1

Procedure:
3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-4-ylamine (1 equivalent), methanesulfonyl chloride (1.1 equivalent), and diisopropylethylamine (2 equivalents) in CH2Cl2 are stirred for 18 hours. The solvent is evaporated, and the resulting residue is purified by preparatory HPLC to provide the title compound.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:5]1[CH:10]=[C:9]([C:11](OCC)=[O:12])[CH:8]=[CH:7][N:6]=1)[CH3:4]>C(O)C.ClCCl>[CH2:3]([C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][N:6]=1)[CH3:4]
Reactant: CCOC(=O)c1ccnc(CC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCc1cc(CO)ccn1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
5.36 g of sodium borohydride are added portionwise to a solution of 5.08 g of ethyl 2-ethylpyridine-4-carboxylate in 53 ml of ethanol, under an inert atmosphere of argon at a temperature in the region of 0° C. The reaction mixture is refluxed with stirring for 3 hours and then concentrated to dryness under reduced pressure. The residue thus obtained is taken up in 500 ml of dichloromethane and then washed with 500 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. 3.16 g of 2-ethyl-4-(hydroxymethyl)pyridine are thus obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24]C3C=CC=C(C#N)C=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.[C:34]([C:36]1[CH:43]=[CH:42][C:39](CBr)=[CH:38][CH:37]=1)#[N:35]>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:39]3[CH:42]=[CH:43][C:36]([C:34]#[N:35])=[CH:37][CH:38]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)cc1

Procedure:
Title compound 19 was prepared by the methods used in the preparation of compound 17, except that p-cyano-benzyl bromide was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3—CD3OD 10:1) δ 7.70 (d, J=7.8 Hz, 1H), 7.56-7.63 (m, 3H), 7.46 (m, 3H), 7.29 (d, J=7.8 Hz, 1H), 5.47 (s, 1H), 5.16-5.36 (ABq, J=51.1, 14.7 Hz, 2H), 5.11 (s, 2H), 3.36-3.47 (m, 2H), 2.90-3.07 (m, 2H), 2.79 (s, 1H), 2.15 (s, 1H), 1.95 (s, 1H), 1.73 (s, 2H). MS (ES) [m+H] calc'd for C25H25N6O2, 441.2; found 441.2.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][C:11]1[CH:10]=[CH:9][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(OCCCC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOc1ccc(Br)c(OCCCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
80 g of 1,3-dibutoxybenzene (0.36 mol) are dissolved at room temperature in 100 ml of carbon tetrachloride. 64.25 g of N-bromosuccinimide (0.36 mol) are introduced in portions over 30 minutes such that the temperature can be maintained between 20° C. and 30° C. When the addition is complete, the mixture is stirred at room temperature for 1 hour. The reaction mixture is filtered over kieselguhr and the solvent is removed completely by concentration. The crude product (110 g) is fractionated on a 10 cm Vigreux column at 10-1 mbar. In this way, 65 g of 1-bromo-2,4-dibutoxybenzene with a boiling point of 112° C. at 10-1 mbar are obtained as a yellowish oil in 60% yield.