Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.CN(C=O)C.O1CCOCC1>CO.Cl.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>[N:4]1[CH:3]=[C:2]([C:16](=[O:18])[CH3:17])[N:6]2[C:5]=1[CH:10]=[CH:9][CH:8]=[N:7]2
Reactant: Brc1cnc2cccnn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)c1cnc2cccnn12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-Bromoimidazo[1,2-b]pyridazine (1.0 g, 5.05 mmol), tributyl(1-ethoxyvinyl)tin (3.41 mL, 10.1 mmol), and PdCl2(PPh3)2 (354 mg, 0.505 mmol), were added to a sealed tube. DMF (25.2 mL) was added and the reaction purged with nitrogen for 5 minutes. The reaction was heated at 100° C. for 18 h. The reaction was cooled to room temperature and quenched with aqueous saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (×3) and the combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with methanol (10 mL) and HCl in 1,4-dioxane (1.26 mL, 5.05 mmol, 4M) was added. The solution was stirred at room temperature for 1 h. The reaction was then quenched with aqueous saturated sodium bicarbonate and extracted with ethyl acetate (×3). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 8.76 (d, 1H); 8.55 (s, 1H); 8.31 (d, 1H); 8.49 (dd, 1H); 2.64 (s, 3H). LRMS (APCI) calc'd for (C8H7N3O) [M+H]+, 162.1. found 162.1.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=2)=[CH:15][C:14]=1[N+:28]([O-:30])=[O:29]>CS(C)=O>[CH2:26]([O:25][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:14]([N+:28]([O-:30])=[O:29])[CH:15]=2)[CH:24]=[CH:23][CH:22]=1)[CH3:27]
Reactant: COC(=O)CC(=O)OC
Reactant: CCOc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOc1cccc(-c2ccc(C(C(=O)OC)C(=O)OC)c([N+](=O)[O-])c2)c1
Temperature: 100 °C

Procedure:
Dimethyl malonate (11.4 mL) was added dropwise to 4.0 g sodium hydride suspended in 20 mL dimethylsulfoxide. The mixture was heated to 100° C. for 10 minutes and then cooled to room temperature. Crude 4-fluoro-3′-ethoxy-3-nitrobiphenyl (5.3 g) in 25 mL of dimethylsulfoxide was added and the mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled and quenched with 300 mL of saturated ammonium chloride solution and extracted three times with ethyl acetate. The extracts were combined, washed with water and brine and then dried over anhydrous sodium sulfate and concentrated to give crude dimethyl 3′-ethoxy-3-nitrobiphenyl-4-malonate as a yellow oil.
Reaction SMILES: O.Cl.[F:3][C:4]([F:26])([F:25])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[C:10]2[NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.CN(C)C=O.[NH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH3:40])[CH2:34]1.C(=O)([O-])[O-].[Na+].[Na+]>S(Cl)(Cl)=O.C(Cl)(Cl)Cl.O>[CH2:39]([N:35]1[CH2:36][CH2:37][CH2:38][CH:33]([NH:32][C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:10]3[C:9]4[C:14](=[C:5]([C:4]([F:25])([F:26])[F:3])[CH:6]=[CH:7][CH:8]=4)[N:13]=[CH:12][CH:11]=3)=[CH:24][CH:23]=2)[CH2:34]1)[CH3:40]
Reactant: O=C(O)c1ccc(Nc2ccnc3c(C(F)(F)F)cccc23)cc1
Reactant: CCN1CCCC(N)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCCC(NC(=O)c2ccc(Nc3ccnc4c(C(F)(F)F)cccc34)cc2)C1
Reaction time: 2 h
Yield: 36.9 %

Procedure:
11.6 Grams (0.03 mole) of 4-(8-trifluoromethyl-4-quinolylamino)benzoic acid hydrochloride monohydrate were refluxed in thionyl chloride containing a few drops of dimethyl formamide for one hour. The thionyl chloride was evaporated and 50 milliliters of benzene were added and evaporated. The resulting acid chloride hydrochloride was added in portions with stirring to a cooled mixture of 3.84 grams (0.03 mole) of 3-amino-1-ethylpiperidine in 80 milliliters of chloroform and 31.8 grams (0.3 mole) of sodium carbonate in 100 milliliters of water. The product began to precipitate almost at once, and the mixture was stirred vigorously for two hours, and allowed to stand overnight. Filtration gave a solid which was stirred in water, collected and dried. The resulting solid was dissolved in an ethanol:chloroform mixture and chromatographed on an alumine column made up in chloroform. Elution with chloroform gave 4.9 grams (37%) of title compound as a pale yellow solid, melting point 177°-178° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:8]([CH2:20]Cl)[CH:7]=1.O>CN(C=O)C>[N:1]([CH2:20][C:8]1[CH:7]=[C:6]([Br:5])[CH:19]=[CH:18][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1cc(Br)ccc1OCCN1CCCC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(Br)ccc1OCCN1CCCC1
Temperature: 35 °C
Reaction time: 16 h

Procedure:
0.33 g (5.00 mmol) of sodium azide were added to a solution of 500 mg (1.57 mmol) of 1-[2-(4-bromo-2-chloromethylphenoxy)ethyl]pyrrolidine in 5 mL of DMF and the mixture was stirred for 16 hours at 35° C. Water was added and the phases were separated. The aqueous phase was exhaustively extracted with DCM, and the combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was used in the next reaction step without any further purification. Yield: 0.42 g (82% of theoretical); C13H17BrN4O (M=325.204); HPLC-MS: 5.62 minutes (method A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]cc(I)c2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.8 %

Procedure:
To 5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (2, 16.50 g, 59.25 mmol) in 250.0 mL of N,N-dimethylformamide, sodium hydride (3.10 g, 60% in mineral oil, 77.5 mmol) was added. The reaction was stirred at room temperature for 90 minutes, then triisopropysilyl chloride (3, 13.00 mL, 61.36 mmol) was added slowly. The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (4, 10.0 g). 5-fluoro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine is prepared similarly from 5-fluoro-3-iodo-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C(NC1C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1)(=O)C>C(#N)C>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8](=[O:15])[C:9](=[N+:37]=[N-:38])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)c1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-(3-chloro-2-fluorophenyl)-3-oxopropanoate (1.30 g, 5.31 mmol), triethylamine (0.618 g, 6.11 mmol, 1.15 equiv), and 4-acetamidobenzenesulfonyl azide (1.40 g, 5.85 mmol, 1.1 equiv) were combined in acetonitrile (15 mL). After stirred at ambient temperature for 30 minutes, the mixture was concentrated in vacuo and the residue was treated with sodium hydroxide (25 mL, 2 M aqueous) and extracted with twice chloroform. The combined organic extracts were washed once with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 40:60; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13].[N+:25]([C:28]1[CH:38]=[CH:37][C:31]([CH2:32][O:33][C:34](Cl)=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26].[OH-].[Na+]>O.O1CCCC1>[OH:11][C@H:9]1[CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[C@H:6]([C:2]2[N:1]([C:34]([O:33][CH2:32][C:31]3[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:38][CH:37]=3)=[O:35])[CH:5]=[CH:4][N:3]=2)[CH2:10]1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1c1ncc[nH]1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1c1nccn1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 63 %

Procedure:
To a solution of (2S,4R)-2-(imidazol-2-yl)-4-hydroxy-1- (4-nitrobenzyloxycarbonyl)pyrrolidine (1.0 g) in a mixture of water (10 ml) and tetrahydrofuran (20 ml) was dropwise added a solution of 4-nitrobenzyloxycarbonyl chloride (0.85 g) in tetrahydrofuran (5 ml) under ice-cooling with stirring, keeping the pH between 9 and 10 with 4N aqueous sodium hydroxide. The mixture was stirred under the same condition for 1 hour, extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give (2S, 4R)-4-hydroxy-2-[N-(4-nitrobenzyloxycarbonyl) imidazol-2-yl]-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (970 mg).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]2=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=[C:4]2[N:3]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.CN(C=O)C>O.C(OCC)(=O)C>[CH3:1][C:2]1[O:7][C:6]([CH3:8])([CH3:9])[C:5]2[C:10]([O:14][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=3)=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC1=Nc2cccc(O)c2C(C)(C)O1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC1=Nc2cccc(Oc3ccc([N+](=O)[O-])cn3)c2C(C)(C)O1
Temperature: 70 °C
Yield: 27.8 %

Procedure:
To a suspension of 2,4,4-trimethyl-4H-3,1-benzoxazin-5-ol (Intermediate 202, 500 mg, 2.61 mmol) and 2-chloro-5-nitropyridine (410 mg, 2.58 mmol) in dry DMF (4 mL) potassium carbonate (400 mg, 2.89 mmol) was added and the resulting mixture was heated in a MW apparatus at 70° C. for 40 min. The mixture was diluted with water and ethyl acetate, phases were separated and the aqueous was back-extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated and the residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate from 70:30 to 50:50 as eluents affording the title compound (225 mg) as yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=2)[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccc(C(C)C)cc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-3-{1-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-2-ethoxy-propionic acid ethyl ester, which was subsequently saponified to yield rac-3-{1-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-2-ethoxy-propionic acid as light green solid.
Reaction SMILES: C([O:4][CH:5]1[C:11]2[CH:12]=[N:13][CH:14]=[N:15][C:10]=2[C:9]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:8]=2[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])=[N:6]1)(=O)C.CO.[OH-].[Na+]>O1CCCC1>[Cl:20][C:18]1[CH:17]=[CH:16][C:9]2[C:10]3[N:15]=[CH:14][N:13]=[CH:12][C:11]=3[CH:5]([OH:4])[N:6]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:8]=2[CH:19]=1
Reactant: CC(=O)OC1N=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: OC1N=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.7 g (9.7 mmole) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-5-ol acetate in a mixture of 25 ml of tetrahydrofuran, 50 ml of methanol and 2 ml of 3N sodium hydroxide was stirred at room temperature for 0.5 hr. The reaction mixture was poured into ice water and extracted with methylene chloride. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue crystallized from a mixture of methylene chloride and ether to give a crude product melting at 186°-188° C. Recrystallization from a mixture of ether and methylene chloride gave the product as cream colored prisms, mp 196°-198° C.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([CH3:21])[S:19][CH:20]=2)=[CH:12][CH:11]=1)[C:3]([O-:5])=[O:4].[Na+].Cl>O>[CH3:1][C:2]([CH3:22])([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([CH3:21])[S:19][CH:20]=2)=[CH:12][CH:11]=1)[C:3]([OH:5])=[O:4]
Reactant: Cc1nc(-c2ccc(OCCCC(C)(C)C(=O)[O-])cc2)cs1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1nc(-c2ccc(OCCCC(C)(C)C(=O)O)cc2)cs1

Procedure:
In 50 ml of water was dissolved 1.0 g of sodium 2,2-dimethyl-5-[p-(2-methyl-4-thiazolyl)phenoxy]pentanoate obtained in EXAMPLE 22. The solution was neutralized with 10% hydrochloric acid. The precipitated crystals were taken out by filtration and washed with water to give the desired product, 2,2-dimethyl-5-[p-(2-methyl-4-thiazolyl)phenoxy]pentanoic acid as white crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11][CH3:12])C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:11]([C:10]1[O:9][C:8]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[N:7][C:6]=1[CH2:5][CH2:4][OH:3])[CH3:12]
Reactant: CCOC(=O)Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Yield: 78.6 %

Procedure:
[5-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-acetic acid ethyl ester (4.0 g, 12.22 mmol) in anhydrous tetrahydrofuran (100 mL) is cooled to 0° C. and a 1M LiAlH4 (12.2 mL, 12.2 mmol) solution is added slowly. The reaction is monitored by TLC until complete consumption of the starting material. The reaction is then carefully quenched with 2.4 mL water, 2.4 mL 5N NaOH and 7 mL water. The light tan solid is filter through celite and dried to give crude 2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethanol (2.74 g, 9.60 mmol) or 79% yield.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@H:11]2[C@H:15]([O:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=3[CH2:27][N:28]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH3:29])[CH2:14][O:13][CH2:12]2)=O)=CC=1)([O-])=O.[OH-].[K+]>CO>[F:23][C:22]1[C:17]([O:16][C@H:15]2[C@@H:11]([OH:10])[CH2:12][O:13][CH2:14]2)=[C:18]([CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[CH:21]=1)[CH2:27][N:28]([CH3:29])[C:30](=[O:31])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1COC[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1COC[C@@H]1O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To 27D (250 mg, 0.439 mmol) in MeOH (5 mL) was added KOH (0.878 mL, 0.878 mmol) and the reaction was stirred at rt for 2 h. The reaction was concentrated and acidified with 1N HCl after addition of H2O. The sample was extracted with EtOAc (2×) and the extracts was washed with sat. NaHCO3 and brine. The solvent was removed and the residue was purified by flash column chromatography (0-60% EtOAc/hexanes) to afford 27E (172 mg, 0.409 mmol, 93% yield). MS (ESI) m/z: 421.4 (M+H)+. 1H NMR (400 MHz, CDCl3)) δ ppm 7.83-8.07 (m, 2H) 7.33 (s, 5H) 5.14 (s, 2H) 4.92-5.03 (m, 1H) 4.78 (d, J=7.91 Hz, 1H) 4.70 (d, J=14.94 Hz, 1H) 4.49-4.60 (m, 1H) 4.39 (d, J=6.15 Hz, 1H) 4.06-4.19 (m, 1H) 3.90-4.03 (m, 2H) 3.65-3.78 (m, 1H) 2.84 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[CH:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1)([CH3:12])[CH3:11].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=2)[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: Cc1cccc(Cl)c1O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cc2ccc(C(C)C)cc2)cc(Cl)c1O
Temperature: 60 °C
Reaction time: 5.5 h

Procedure:
85.8 g (0.6 mol) 2-chloro-6-methylphenol and 33.8 g (0.2 mol) 4-isopropylbenzyl chloride, dissolved in 160 ml chloroform, are reacted with 18 g water-free zinc chloride. At a bath temperature of 60° C. the reaction mixture is stirred 5-6 h, and then washed three times each with 150 ml water for the purpose of removing excess zinc chloride, dried across sodium sulfate and subjected to a driving-off of the solvent chloroform in a vacuum.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@H:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:8][C@H:9]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H](O)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCc1ccccc1)OS(C)(=O)=O
Reaction time: 0.67 h
Yield: 99.6 %

Procedure:
Triethylamine (583 mg) was added dropwise to a stirred mixture of ethyl (R)-2-hydroxy-4-phenylbutyrate (1.0 g) and methanesulfonyl chloride (660 mg) in dichloromethane (10 ml) at ice-bath temperature. After 40 minutes, the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give ethyl (R)-2-methylsulfonyloxy-4-phenylbutyrate (1.37 g) as an oil. This material was used immediately without further purification. NaH (60% in mineral oil, 192 mg) was added to a solution of 4-imidazolecarboxamide (534 mg) in DMF (8 ml) at room temperature. The reaction mixture was stirred for 30 minutes. The methanesulfonate prepared above was added and the resulting mixture was stirred for 3 hours at 60° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)C.Cl.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1>C(O)CCC.C(OC)(C)(C)C>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:31]=[CH:32][C:33]([N:36]2[C:4](=[O:3])[C:6]3=[C:7]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=4)[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]3=[N:37]2)=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nc2ccccc2c1Cl
Reactant: COC(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: COC(=O)c1ccc(-n2nc3c4ccccc4[nH]c(-c4ccc([N+](=O)[O-])cc4)c-3c2=O)cc1
Yield: 76.6 %

Procedure:
4-Chloro-2-(4-nitrophenyl)-quinoline-3-carboxylic acid ethyl ester (2.86 g, 0.008 mol) and 4-hydrazino-benzoic acid methyl ester hydrochloride (1.7 g, 0.008 mol) were stirred in n-butanol (70 mL) at 120° C. for 24 h. The bright orange suspension was diluted with tert-butylmethyl ether, filtered, washed with cold heptane and left to dry under suction to yield 4-[4-(4-nitrophenyl)-3-oxo-3,5-dihydropyrazolo[4,3-c]quinolin-2-yl]-benzoic acid methyl ester (2.7 g, 76%) as an orange solid, LCMS m/z 441.35 [M+H]+ @ RT 1.66 min: 84% purity.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([NH:17][CH2:18][CH2:19]Cl)=[O:16])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[H-].[Na+]>O1CCCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][NH:17][C:15]2=[O:16])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC(=O)NCCCl)c1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(N2CCNC2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of {3-[3-(2-chloro-ethyl)-ureido]-phenyl}-carbamic acid tert-butyl ester (1 g, 3.2 mmol) and potassium carbonate (1.32 g, 9.6 mmol) in dry tetrahydrofuran (20 ml) were stirred at room temperature overnight. No reaction was observed. Sodium hydride (260 mg, 6.5 mmol, 60% dispersion in oil) was then added and reaction stirred at room temperature overnight. Reaction was quenched with water (50 ml) then extracted with dichloromethane (3×50 ml). The combined organics were dried (magnesium sulphate) and concentrated in vacuo. HPLC retention time 7.0 min. Mass spectrum (ES+) m/z 295 (M+NH4)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=2)=[CH:3][CH:2]=1.I[CH2:19][CH2:20][CH3:21]>>[CH2:19]([N:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14]([F:15])([F:16])[F:17])[CH:8]=2)[CH2:3][CH2:2]1)[CH2:20][CH3:21]
Reactant: CCCI
Reactant: Nc1ccc(-c2ccncc2)cc1C(F)(F)F
Product: CCCN1CC=C(c2ccc(N)c(C(F)(F)F)c2)CC1
Temperature: 100 °C

Procedure:
4-Pyridin-4-yl-2-trifluoromethyl-phenylamine (270 mg) was dissolved in 1-iodo-propane (2 ml) and heated to 100° C. for 2 h. Then the voilatiles were evaporated and the residue redissolved in abs EtOH (20 ml) and NaBH4 (800 mg) was added portions wise at −20° C. The mixture was then allowed to reach r.t. and stirred over night. To the mixture was added 10% Na2CO3 solution (20 ml). The aqueous layer was extracted with CH2Cl2 and the combined organic phases were dried (MgSO4), filtered and evaporated to dryness. The crude product was purified by flash chromatography (MeOH: CH2Cl2 (1:9 (v/v)). Collection of the fractions containing pure product and evaporation of the solvent afforded pure 4-(1-Propyl-1,2,3,6-tetrahydro-pyridine-4-yl)-2-trifluoromethyl-phenylamine (200 mg). MS m/z (rel. intensity, 70 eV)) 284 (M+, 53), 255 (bp), 144 (40), 127 (39), 70 (39). Rf 0.28 (MeOH)