Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:31])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].[OH-].[Na+].Cl.CCOC(C)=O>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:31])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)NCCc3ccc(Cl)cc3)cc1)c2Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(Oc2c(Cl)cc3c(c2Cl)OCCC3C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.1 %

Procedure:
Ethyl 6,8-dichloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate (26.8 g, 48.83 mmol) was dissolved in 200 proof EtOH (50 ml)-THF (170 ml). 6N NaOH solution (12.21 ml, 73.25 mmol) was added to the mixture at ambient temperature. The mixture was stirred for 1 hour at ambient temperature. The mixture was transferred to a separatory funnel. 1N HCl solution (97.66 ml, 97.66 mmol) was added to the separatory funnel and EtOAc (100 ml) was added. The mixture was shaken and stood for layer separation. The layers were separated and the organic layer was washed with water and brine (100 ml), dried over MgSO4, filtered, and concentrated to provide 28 g of foamy brown solid after drying under high vacuum. The crude solid was recrystallized from THF-hexanes to provide 22.8 g of the title compound as a white solid (89%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C=O)C.O1CCOCC1.[Br:23][CH2:24][C:25](Br)=[O:26]>O>[Cl:11][C:10]1[C:2]([NH:1][C:25](=[O:26])[CH2:24][Br:23])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(Br)CBr
Reactant: Nc1c(Cl)cccc1C(=O)O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CBr)Nc1c(Cl)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A solution of 2-amino-3-chlorobenzoic acid (7 g, 0.041 mol), anhydrous DMF (20 mL) and anhydrous dioxane (20 mL) was cooled to 0° C. in a 250 mL 3-necked flask, fitted with a magnetic stirrer and constant additional funnel. Bromoacetyl bromide was added dropwise over a 27 min period, keeping the internal temperature between 0° to 2° C. After the addition was complete, the solution was allowed to warm to room temperature and stirring was continued for 4 hours. The reaction mixture was cooled in an ice-bath and diluted with water (100 mL). The resulting yellow precipitate was filtered, washed with water and dried in vacuum oven for 2 days, affording 7.7 g (65%) of the title compound as a light yellow crystals, mp 173-175° C.; 1H NMR (CD3OD) δ 7.88 (dd, 1H, J=1.6, J=6), 7.68 (dd, 1H, J=1.2, J=6.8), 7.39 (t, 1H, J=8); 13C NMR (CD3OD) δ 176.37, 168.38, 134.84, 134.40, 131.95, 130.53, 129.15, 129.05, 28.66; MS (EI, m/z) 293 (M+).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17](Cl)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: CC(Cl)Cl
Product: CCCCCC(=O)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 46.2 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.69 mmol), hexanoyl chloride (0.098 mL, 0.69 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (8 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)hexanamide (0.10 g). MS (ESI) m/z 314 ([M+H]+).
Reaction SMILES: [C:1](O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\C/C=C\CCCCC.C(=O)CCCCC.C(O)CCCCC>>[CH:1](=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCCCCC=O
Solvent: CCCCCCO
Product: CCCCCC=CC=CC=O

Procedure:
In accordance with the invention, soybean seed are provided containing lipoxygenases 1, 2 and 3 and greater than about 10% linoleic acid as a percentage to total fatty acids that produces less than 20 μg of total 2,4 decadienal plus hexanal plus hexanol per gram of ground seeds following oxidation under mild aqueous conditions.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]3[S:15][C:14]([C:16]([O:18]C)=[O:17])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1.[Li+].[OH-].Cl>C1COCC1.CO.C(OCC)C>[O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]3[S:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: COC(=O)c1ccc(-c2cccc3c2CNC3=O)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: O=C(O)c1ccc(-c2cccc3c2CNC3=O)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.6 %

Procedure:
A suspension of Example 127A (0.34 g, 1.24 mmol) in THF (30 mL) and methanol (30 mL) was treated with 1N LiOH (10 mL), stirred at room temperature for 5 hours, then acidified with 1N HCl and diluted with diethyl ether. The resulting suspension was filtered and the filter cake was washed with water and dried to give 288 mg of the desired product. MS (ESI(−)) m/e 258 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[C:15]=1I)=[O:4].[Li+].[CH3:20]CC[CH2-].CI>O1CCCC1>[F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[C:15]=1[CH3:20])=[O:4]
Reactant: [CH2-]CCC
Reactant: O=C(Nc1nc2ccc(F)cn2c1I)C(F)(F)F
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(NC(=O)C(F)(F)F)nc2ccc(F)cn12
Temperature: -78 °C

Procedure:
2,2,2-trifluoro-N-(6-fluoro-3-iodoimidazo[1,2-a]pyridin-2-yl)acetamide (0.500 g, 0.00134 mol) was dissolved in tetrahydrofuran (16 mL) and was cooled at −78° C. N-Butyllithium (2 molarin cyclohexane, 1.6 mL) was added and the reaction was warmed to −20 for 15 minutes then chilled to −78° C. Methyl iodide (110 uL, 0.0017 mol) was added and the reaction was allowed to warm to room temperature. The reaction was poured into ice water and extracted with ethyl acetate (3×50 mL). The combined organics were dried (magnesium sulfate) and solvent removed. Residue chromatographed on silica (50% ethyl acetate/hexanes) to give 2,2,2-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)acetamide 5 Rf 0.47, 50% ethyl acetate/hexanes; MS m/z 262 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[CH:20]1([S:26](Cl)(=[O:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([NH:8][S:26]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:28])=[O:27])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NS(=O)(=O)C1CCCCC1

Procedure:
The title compound was synthesized substantially in the same manner as Example 3 by coupling of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) with cyclohexanesulfonyl chloride (0.053 g, 0.288 mmol) in dichloromethane (3 mL) and pyridine (0.500 mL) to obtain 0.0195 g (50%) of the compound.
Reaction SMILES: Br[CH2:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])=O.[CH:28]([NH2:30])=[S:29].C(OCC)(=O)C>CO.ClCCl>[CH3:14][S:11]([O:10][C@H:8]1[CH2:7][N:6]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:5]([C:3]2[N:30]=[CH:28][S:29][CH:2]=2)[CH2:9]1)(=[O:12])=[O:13]
Reactant: NC=S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)CBr)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2cscn2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 4 h
Yield: 88 %

Procedure:
To a mixture of (2S,4R)-2-bromoacetyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.15 g) in a mixture of methanol (20 ml) and dichloromethane (15 ml) was added thioformamide (453 mg) at room temperature. After stirring at the same temperature for 4 hours, the mixture was poured into ethyl acetate and washed in turn with saturated aqueous sodium bicarbonate and brine. The dried organic layer was evaporated and the resulting oil was crystallized from a mixture of n-hexane and dichloromethane (100:1 V/V) to give (2S,4R)-4-methanesulfonyloxy-2-(thiazol-4-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (930 mg).
Reaction SMILES: [BH4-].[Na+].[CH2:3]1[CH2:30][O:29][C:5]([C@@H:7]2[C@:24]3([CH3:25])[C@H:10]([C@H:11]4[C@H:21]([C:22](=[O:26])[CH2:23]3)[C@:19]3([CH3:20])[C@H:14]([CH2:15][C@H:16]([OH:27])[CH2:17][CH2:18]3)[CH2:13][CH2:12]4)[CH2:9][C@H:8]2[CH3:28])([CH3:6])[O:4]1.C(O)(=O)C>O.C(O)C.N1C=CC=CC=1>[CH2:30]1[CH2:3][O:4][C:5]([C@@H:7]2[C@:24]3([CH3:25])[C@H:10]([C@H:11]4[C@H:21]([C@@H:22]([OH:26])[CH2:23]3)[C@:19]3([CH3:20])[C@H:14]([CH2:15][C@H:16]([OH:27])[CH2:17][CH2:18]3)[CH2:13][CH2:12]4)[CH2:9][C@H:8]2[CH3:28])([CH3:6])[O:29]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]2(C)[C@H]1C1(C)OCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: c1ccncc1
Product: C[C@@H]1C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C1(C)OCCO1
Yield: 43.4 %

Procedure:
A solution of sodium borohydride (4.12 g) in water (41 ml) was added to a refluxing solution of 20,20-ethylenedioxy-3α-hydroxy-16α-methyl-5α-pregnan-11-one (7.55 g) in ethanol (375 ml) containing pyridine (7 drops). The mixture was refluxed for 1 hr. then cooled and glacial acetic acid added until no further effervescence occurred. The mixture was partitioned between 3%-aqueous sodium hydrogen carbonate and ethyl acetate. The aqueous portion was extracted with additional ethyl acetate. The combined organic extracts were washed with saturated brine solution, dried and evaporated to a white foam which crystallised from acetone-water to afford the title compound as white prisms (3.29 g),
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:13]3[CH2:14][CH:10]([CH2:11][N:12]3C(OC(C)(C)C)=O)[CH2:9][CH:8]=2)[O:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:13]3[CH2:14][CH:10]([CH2:11][NH:12]3)[CH2:9][CH:8]=2)[O:4][N:3]=1
Reactant: Cc1cc(C2=CCC3CC2N(C(=O)OC(C)(C)C)C3)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2=CCC3CNC2C3)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A solution of tert-butyl 4-(3-methyl-5-isoxazolyl)-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate (80 mg, 0.28 mmol) in 10 mL of dichloromethane was treated with trifluoroacetic acid (2 mL) with ice bath cooling. After stirring 2 h and warming to ambient temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was made basic with 10% potassium hydroxide solution and extracted with chloroform (2×10 mL). The extracts were dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product as a viscous oil (30 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([C@@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:9]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH:5]=[CH:6][CH:7]=1.IC.[CH3:34][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH:12]([CH3:34])[C:11](=[O:14])[N:10]([C@@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:9]2[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 11.2 g (24.2 mmol) of (S)-tert-butyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate (Example 66, Step A) and iodomethane (1.813 mL, 29.1 mmol) in THF (120.0 mL) was added a lithium bis(trimethylsilyl)amide, (1M solution in THF; 26.6 mL, 26.6 mmol) at −78° C. The reaction was allowed to warm to R.T., then was quenched (sat. aqueous NH4Cl) and extracted (2×EtOAc). The combined organic layers were washed with water and sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was absorbed onto a plug of silica gel and purified by chromatography on silica gel, eluting with a gradient of 10% to 30% EtOAc in hexane, to provide the title compound as a mixture of stereoisomers.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[C:7]([O:30][CH3:31])[CH:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[C:7]([O:30][CH3:31])[CH:6]=1
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
1,1-Dimethylethyl 7-{[4-[(methylamino)carbonyl]-2-(methyloxy)phenyl]oxy}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (E264, Step 5) (100 mg, 0.23 mmol) was dissolved in dry dichloromethane (2 ml), treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue dissolved in methanol and applied to a SCX column eluting with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The basic fractions were combined and concentrated in vacuo to afford the title compound (78 mg); MS (ES+) m/e 327 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][C:7]([CH3:20])=[N:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[Se](=O)=[O:24]>O1CCOCC1>[CH:20]([C:7]1[CH2:6][C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:9][N:8]=1)=[O:24]
Reactant: O=[Se]=O
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2C1
Solvent: C1COCCO1
Product: O=CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2C1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
9.17 g (29.0 mM) of 8-chloro-4-methyl-1-(4-nitrophenyl)-5H-2,3-benzodiazepine (prepared according to the method described in Example 39) were dissolved in 120 ml of dioxane, then 2.27 g (20.5 mM) of selenium dioxide powder were added and the mixture was stirred on a 90° C. water bath for 40 minutes. Then the solution was treated with active carbon, filtered and poured into 1500 ml of water. The precipitated crystals were filtered and washed with water. The crude product was purified on a Kieselgel column using benzene as eluant.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[Br:6][C:7]1[C:12]2[CH:13]=[C:14](CO)[O:15][C:11]=2[C:10]([O:18][CH3:19])=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:1][Br:5])[O:15][C:11]=2[C:10]([O:18][CH3:19])=[CH:9][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(Br)c2cc(CO)oc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(Br)c2cc(CBr)oc12
Reaction time: 1 h
Yield: 62.7 %

Procedure:
Carbon tetrabromide (1.52 g) was added to a stirred solution of (4-bromo-7-methoxybenzofuran-2-yl)-methanol (1 g) in dichloromethane (10 ml) at 0° C. under an inert atmosphere. Triphenylphosphine (1.53 g) was then added and the reaction stirred for 1 h. The reaction mixture was preadsorbed onto silica and purified by column chromatography eluting with 25% ethyl acetate in hexane to afford the title compound as a yellow solid (0.78 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O.C(N(CC)CC)C.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(Cl)Cl>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][N:38]([CH2:2][C:3]2[N:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]3=[N:5][C:4]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:37][CH2:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1-c1nc2ccccn2c1CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(-c3ccccc3N)nc3ccccn23)CC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 66.7 %

Procedure:
To 3-Chloromethyl-2-(2-nitro-phenyl)-imidazo[1,2-a]pyridine (298 mg, 0.92 mmol) suspended in CH2Cl2 (15 ml) cooled to 0° C. was added dropwise triethylamine (279 mg, 3 eq), followed by 1-Boc-piperazine (1.3 eq, 221 mg) in two portions over a 24 hour period. The reaction mixture was concentrated to dryness and purified by chromatography using a 9:1 mixture of CH2Cl2 to MeOH. The fractions were concentrated, dissolved in Ethanol (20 ml), and stirred over H2 atmosphere with 10% Pd/C (10 mg) for 48 hours. The reaction mixture was filtered through Celite and concentrated, and dried under high vacuum to obtain 250 mg of the desired product. (MS, M++H=408.2)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=2)[CH:2]=1.[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: CCOC(=O)c1ccc(-c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of the obtained ethyl 4-(3-pyridyl)benzoate (2.14 g) in ethanol (20 ml) was added 1 N sodium hydroxide solution (15 ml), and the solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and the residue was dissolved in water, to which was added 1 N hydrochloric acid (15 ml). The precipitate was filtered, washed with water and dried to give the title compound (1.488 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12](I)=[CH:11][C:10]=2[F:18])=[O:5])[CH3:2].[C:19]1([CH3:28])[C:20](B(O)O)=[CH:21][CH:22]=[CH:23][CH:24]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:28])=[CH:11][C:10]=2[F:18])=[O:5])[CH3:2]
Reactant: Cc1ccccc1B(O)O
Reactant: CCOC(=O)c1cnc2c(F)cc(I)cc2c1O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(F)cc(-c3ccccc3C)cc2c1O
Temperature: 80 °C
Yield: 47 %

Procedure:
6-Iodo-8-fluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester (903 mg) from Example No. 5 and o-tolueneboronic acid (374 mg) are dissolved in DMF (50 mL) and at 50° C. a solution of barium hydroxide octahydrate (1.18 g) in water (5 mL) is added followed by palladium tetrakistriphenylphosphine (58 mg). The mixture is heated at 80° C. for 20 h, allowed to cool to rt, poured into water (200 mL), and extracted with ethyl acetate (3×100 mL). The organic layer is washed with brine (25 mL), dried (MgSO4), and concentrated. The solid is then triturated with MTBE, and filtered to afford 382 mg of 6-(2-methylphenyl)-8-fluoro-4-hydroxy-3-quinoline-carboxylic acid ethyl ester. The crude ester is mixed with 4-chlorobenzylamine (380 mg) and is heated to 190° C. for 1 h. The mixture is diluted with toluene (4 mL), allowed to cool to rt, poured into a mixture of 50% acetic acid (10 mL) and 1 N hydrochloric acid (25 mL), and is extracted with ethyl acetate (3×25 mL). The organic layer is dried (MgSO4) and allowed to crystallize. Recrystallization from acetic acid/water affords 166 mg of the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:3][CH:4]=1
Reactant: C1CCNC1
Reactant: Brc1ccc(Br)c2ccccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Brc1ccc(N2CCCC2)c2ccccc12
Temperature: 70 °C

Procedure:
To a solution of 1,4-dibromonaphthalene (500 mg, 0.002 mol), Pyrrolidine (0.18 mL, 0.0021 mol), (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1-binaphthyl (0.022 g, 0.000035 mol), Sodium tert-butoxide (0.24 g, 0.0024 mol) in Toluene (5.00 mL, 0.0469 mol) was added Tris(dibenzylideneacetone)dipalladium(0) (0.008 g, 0.000009 mol), and the mixture was heated at 70° C. overnight. The reaction was cooled, quenched by addition of water and the mixture was extracted with DCM (3×), washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 25% hexanes/DCM) to obtain 400 mg (80%). Reference: Jean, L.; Rouden, J.; Maddaluno, J.; Lasne, M-C. J. Org. Chem. 2004, 69, 8893-8902.
Reaction SMILES: [NH:1]1[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[CH2:3][CH2:2]1.[C:14]1([C:20](Cl)([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)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:20]([N:1]1[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[CH2:3][CH2:2]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(=O)CCc1cnn2c1NCC2
Solvent: c1ccncc1
Product: NC(=O)CCc1cnn2c1N(C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Temperature: 60 °C
Reaction time: 17 h
Yield: 79.6 %

Procedure:
To a solution of 3-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)propanamide (6 g) in pyridine (60 ml) was added triphenylmethyl chloride (11.1 g) at room temperature. The mixture was stirred at 60° C. for 17 hours. The reaction mixture was evaporated under reduced pressure and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was triturated with diisopropyl ether and dried in vacuo to give 3-(1-trityl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)propanamide (11.2 g).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([NH:13]CC2C=CC=CC=2)[C:9]2[C:21](=[O:29])[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:23][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:30]>C(O)C.C(O)(=O)C.[Pd]>[F:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]2[C:21](=[O:29])[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:23][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:30]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(NCc4ccccc4)c3c1=O)CCN2C
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)CCN2C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
59 mg of the compound (200) obtained in Example 71 was dissolved in 10 ml of ethanol and 10 ml of acetic acid, and 5 mg of 10% palladium on carbon was added to the solution. the solution was stirred for 24 hours under hydrogen. The catalyst was filtered, and the filtrate was evaporated. The residue was dissolved in chloroform and was washed with saturated aqueous sodium hydrogen-carbonate solution. After drying over magnesium sulfate, the solvent was removed by distillation. Solids were dispersed in ether and filtered off to obtain 27 mg of the subject compound (201) in a 59% yield.