Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:29][O:30]CC)[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:29][OH:30])[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)C(=O)NCCCCn1c(CO)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 2.2 %

Procedure:
Boron tribromide (2.5 equivalents, 15.6 mL of 1 M solution in dichloromethane) was added dropwise to a cooled (ice bath) suspension of N-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]isobutyramide (2.4 g, 6.2 mmol) in dichloromethane (25 mL). The reaction mixture was allowed to slowly warm to ambient temperature and then stirred for 1 day. Additional boron tribromide (5 equivalents, 31 mmol, 31 mL) was added to the mixture. The reaction was quenched slowly with methanol (100 mL) and then concentrated under reduced pressure. The residue was combined with 6 M hydrochloric acid (100 mL), heated to 5° C., and stirred for 2 hours. The resulting solution was cooled (ice bath) and then free-based (pH 9) with the addition of 6 M sodium hydroxide. A brown gummy solid formed in the basic aqueous solution. The resulting solid was extracted with dichloromethane (6×50 mL). The combined extracts were washed with brine (100 mL), dried with magnesium sulfate, filtered, and then concentrated under reduced pressure. This material was purified by prep HPLC (Analogix Separation System, Biotage Si 40+M column, eluted with a gradient of 0-20% methanol in dichloromethane with 1% ammonium hydroxide) to provide a light brown solid. The solid was triturated with hot acetonitrile, allowed to cool, isolated by filtration, washed with ether, and dried under vacuum to provide N-[4-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]isobutyramide (0.049 g) as a white solid, mp 222-224° C.; MS (ESI) m/z 356 (M+H)+; Anal. Calcd for C19H25N5O2.0.25HBr.0.10H2O: C, 60.46; H, 6.80; N, 18.55. Found C, 60.26; H, 6.64; N, 18.43.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:36][C:37]1([C:43]2[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)[CH:42]2[CH:38]1[CH2:39][NH:40][CH2:41]2.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:40]1[CH2:41][CH:42]2[CH:38]([C:37]2([C:43]2[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)[CH3:36])[CH2:39]1)=[O:12]
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: O=C(O)CCc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3ccccc3Cl)CC21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 109.1 %

Procedure:
To a solution of 3-(2-chlorophenyl)propanoic acid (200 mg, 1.08 mmol) in N,N-dimethylformamide (20 ml) was added 1-hydroxybenzotriazole monohydrate (187 mg, 1.22 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (318 mg, 1.66 mmol). After stirring at room temperature for 10 min, the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 400 mg, 1.32 mmol) and sodium hydrogen carbonate (200 mg, 2.38 mmol). The reaction mixture was stirred at room temperature for 3 d and then concentrated in vacuo. Water (15 ml) was added and the reaction mixture was extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with water (10 ml), dried (MgSO4), and concentrated in vacuo to afford 510 mg of a light brown oil. Sonication for 5 min at room temperature in dichloromethane (5 ml) followed by filtration afforded the title compound as an off-white solid (124 mg, 27%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28].C(N(CC)CC)C>ClCCl>[CH2:30]([O:29][C:27](=[O:28])[NH:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOC(=O)Cl
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a stirred solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethyl-phenyl)methanone (100 mg, 0.285 mmol) in dichloromethane (5 mL) was added n-butyl chloroformate (0.285 mmol) in the presence of triethylamine (0.313 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 24 h and then quenched with water (10 mL). The organic phase was washed with water, saturated NaCl, dried over MgSO4 and then concentrated in vacuo to afford the desired product as a white solid (0.095 g, 74% yield). 1H NMR (500 MHz, CDCl3) δ 8.10, 7.73, 7.63, 7.55, 7.36, 7.04, 4.19, 3.96-4.02, 3.89-3.95, 3.61-3.66, 3.52-3.56, 3.32, 1.64-1.70, 1.38-1.46, 0.95.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1.[Cl-].[NH4+]>CCOCC>[F:16][C:13]([F:15])([F:14])[C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=1)([OH:17])[CH3:1]
Reactant: C[Mg]Cl
Reactant: COc1ccc(C(=O)C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At −15° C., 18 ml of a 3 M solution of methylmagnesium chloride in ether were added dropwise to a solution of 5.8 g of 4′-methoxy-2,2,2-trifluoroacetophenone in 35 ml of ether, and the mixture was stirred at room temperature for 5 h. The reaction solution was hydrolysed with aqueous ammonium chloride and extracted with ether. The extract was dried and to give the title product as a colourless oil, which was reacted further without any purification.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](B(O)O)[CH2:11][CH3:12]>>[CH2:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: CCCB(O)O
Reactant: O=Cc1ccc(Br)cc1
Product: CCCc1ccc(C=O)cc1
Yield: 29 %

Procedure:
The compound was synthesized as in Example 3.1 using 4-bromobenzaldehyde (250 mg, 1.35 mmol) in place of 5-bromo-2-formylfuran and propylboronic acid (196 mg, 2.23 mmol) in place of hexylboronic acid to give 4-propylbenzaldehyde (58 mg, 29%). Used without further characterization.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]([C:27]([N:29]1[CH2:33][CH2:32][C:31]([F:35])([F:34])[CH2:30]1)=[O:28])[C@H:9]([CH:11]1[CH2:16][CH2:15][C:14](O)([C:17]2[N:22]3[N:23]=[CH:24][N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]([C:27]([N:29]1[CH2:33][CH2:32][C:31]([F:35])([F:34])[CH2:30]1)=[O:28])[C@H:9]([CH:11]1[CH2:16][CH2:15][C:14]([C:17]2[N:22]3[N:23]=[CH:24][N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=2)=[CH:13][CH2:12]1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C1CCC(O)(c2cccc3ncnn23)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: C[C@@H](C1CC=C(c2cccc3ncnn23)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Reaction time: 1 h

Procedure:
To a solution of the compound prepared in Step A (0.13 g, 0.26 mmol) in THF (5 mL) was added Burgess reagent (0.19 g, 0.78 mmol). After 1 h at ambient temperature, the reaction mixture was concentrated to 1 mL in vacuo. The remaining solution was added to saturated aqueous sodium bicarbonate and the resulting mixture was extracted with dichloromethane. The combined organic layers were dried (anhydrous sodium sulfate) and concentrated in vacuo to give the title compound. LC/MS 490.4 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12](Cl)[N:11]=[C:10]([S:18][CH2:19][CH2:20][CH3:21])[N:9]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:7][C:8]1[N:9]=[C:10]([S:18][CH2:19][CH2:20][CH3:21])[N:11]=[C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCSc1nc(Cl)c([N+](=O)[O-])c(N2CCOCC2)n1

Procedure:
Morpholine (2.6 g) was added dropwise to a stirred solution of 4,6-dichloro-5-nitro-2-propylthiopyrimidine (8 g) and N,N-diisopropylethylamine (3.85 g) in acetonitrile (70 ml ) at 0° C. After 1 h the solvent was evaporated and the residue partitioned between ethyl acetate and water, the organics dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 25% ethyl acetate in isohexane. Yield 7.1 g
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][NH:3]1.[H-].[Na+].[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[S:28][C:27]([CH2:29]Br)=[N:26][C:25]=2[CH:31]=1.Cl>CN(C)C=O>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[S:28][C:27]([CH2:29][N:3]3[C:2](=[O:1])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4]3)=[N:26][C:25]=2[CH:31]=1
Reactant: BrCc1nc2cc(Br)ccc2s1
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nn(Cc2nc3cc(Br)ccc3s2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl 4-oxo-3H-phthalazin-1-ylacetate (11.6 g.) and sodium hydride (288 g; 50% w/w dispersion in mineral oil) in dimethylformamide (150 ml) was added 5-bromo-2-bromomethylbenzothiazole (16.8 g) and the resulting mixture stirred at room temperature for 1 hour. This reaction mixture was poured over ice-water (500 ml.); sufficient 10% HCl was added to adjust the pH to about 4.0 and the precipitated crude solid was collected. This was chromatographed over silica gel to obtain the product (yield: 5.6 g; m.p. 160°-161° C.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19].C(N(CC)CC)C>C1COCC1.[Cu]I.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>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1cccc(I)c1NC(=O)OC(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C#C[Si](C)(C)C)c1NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 98 %

Procedure:
To tert-butyl 2-iodo-6-methoxyphenylcarbamate (10.36 g, 29.67 mmol), ethynyltrimethylsilane (3.20 g, 32.63 mmol), copper(I) iodide (0.28 g, 1.48 mmol), and PdCl2(PPh3)2 (1.04 g, 1.48 mmol) in THF (100 mL) was added triethylamine (3.60 g, 35.6 mmol), followed by overnight stirring. The crude reaction was then concentrated and the mixture was flashed through silica gel with 10:1 Hex/EtOAc to give the desired product (98%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[OH-].[Na+].C(OCCO)C.[CH2:16]([O:20][CH2:21][CH:22]=[CH2:23])[CH:17]1[O:19][CH2:18]1>N(C1C=CC(O)=CC=1)=O.O>[OH:19][CH:17]([CH2:16][O:20][CH2:21][CH:22]=[CH2:23])[CH2:18][NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5]
Reactant: C=CCOCC1CO1
Reactant: NCCS(=O)(=O)O
Agent: O=Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCCO
Solvent: O
Product: C=CCOCC(O)CNCCS(=O)(=O)O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 40.2 %

Procedure:
Into a 2 liter volume flask equipped with a stirrer, taurine (125 g), sodium hydroxide (40 g), deionized water (200 g) and ethylene glycol monoethyl ether (600 g) were charged. The contents were maintained at 60° C. while stirring, and a mixture of allyl glycidyl ether (114 g) and p-nitrosophenol (0.1 g) was dropwise added thereto in 20 minutes. Thereafter, stirring was continued for 2 hours. The reaction mixture of pH 9 was treated with an ionic exchange resin (Amberlite IR-120) to eliminate Na+ ion, whereby a solution of pH 4 was obtained. The solution was concentrated in a rotary evaporator to make a 7/10 volume so that needle crystals were precipitated. These crystals were identified to unreacted taurine by NMR and IR. The filtrate was poured into a 3 time volume of acetone to precipitate brown oily materials. The oily materials were collected and dried in vacuo as give N-(2-hydroxy-3-allyloxypropyl)taurine (96 g) of the formula: ##STR7##
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:36])[N:21]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[C:32](=[O:33])[CH:31]=[CH:30][C:29]3=[O:34])=[CH:24][CH:23]=2)[C:20](=[O:35])[CH:19]=[CH:18]1>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:30]2[CH2:31][C:32](=[O:33])[N:28]([C:25]3[CH:26]=[CH:27][C:22]([N:21]4[C:20](=[O:35])[CH2:19][CH:18]([S:11][C:9]5[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=5)[C:17]4=[O:36])=[CH:23][CH:24]=3)[C:29]2=[O:34])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C1C=CC(=O)N1c1ccc(N2C(=O)C=CC2=O)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SC2CC(=O)N(c3ccc(N4C(=O)CC(Sc5cc(C(C)(C)C)c(O)c(C(C)(C)C)c5)C4=O)cc3)C2=O)cc(C(C)(C)C)c1O
Yield: 75.6 %

Procedure:
The procedure of Example 1 is repeated using 17.8 grams of 2,6-di-tert-butyl-4-mercaptophenol, 10 grams of 1,4-bis(maleimido)benzene, and 0.75 grams of triethylamine. The residue is recrystallized from acetone to give 21 grams of an off-white solid, m.p. 274°-278° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[CH3:12][N:13]1[C:22]2[CH2:21][CH2:20][CH2:19][C:18](=O)[C:17]=2[CH:16]=[CH:15][C:14]1=[O:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][CH:18]2[CH2:19][CH2:20][CH2:21][C:22]3[N:13]([CH3:12])[C:14](=[O:24])[CH:15]=[CH:16][C:17]2=3)=[CH:5][CH:4]=1
Reactant: Cn1c2c(ccc1=O)C(=O)CCC2
Reactant: COc1ccc(CCN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCNC2CCCc3c2ccc(=O)n3C)cc1
Temperature: 25 °C
Reaction time: 39 h
Yield: 80.4 %

Procedure:
A mixture of 2-(4-methoxyphenyl)ethylamine (5.6 g), 5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (5.5 g), and a catalytic amount of para-toluenesulfonic acid was heated in refluxing toluene (90 ml), with azeotropic removal of water, for 39 hrs. The solution was cooled and concentrated in vacuo. Sodium borohydride (1.1 g) was added to a solution of the residue in ethyl alcohol (90 ml), and the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo, the residue was quenched with water, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was washed with diethyl ether to afford 7.8 g (81%) of product. Recrystallization from ethyl acetate/hexanes provided the analytical sample, mp 97°-99° C.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:25])[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[O:12]2)=[C:7]([O:26][CH3:27])[CH:6]=1)#[N:2].[Cl-].[NH4+].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[NH:30]1[C:1]([CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9](=[O:25])[CH:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=4)[O:12]3)=[C:7]([O:26][CH3:27])[CH:6]=2)=[N:2][N:32]=[N:31]1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2cc(=O)c3c(OC)cc(OCC#N)cc3o2)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(=O)c3c(OC)cc(OCc4nnn[nH]4)cc3o2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.9 %

Procedure:
7-(cyanomethyloxy)-3′,4′,5-trimethoxy flavone (0.3 g, 0.82 mmol) obtained in Step 2, ammonium chloride (0.13 g, 2.45 mmol) and sodium azide (0.08 g, 1.23 mmol) were dissolved in N,N′-dimethylformamide (6 mL). After the reaction was carried out at 120° C. for 3 hours, the reaction solution was cooled to room temperature. The resulting solids were filtered and washed with ethyl acetate and n-hexane. The washed solids were dissolved in a 3:1 mixed solvent of chloroform and methanol and dried over anhydrous sodium sulfate to remove the solvent. The resulting residue was recrystallized from a 1:1 mixed solvent of ethyl acetate and chloroform to give 0.195 g (yield: 58%) of the title compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:19]1[S:18][C:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=2)=[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH:20]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc(Cl)sc2-c2ccc(OC)cc2)cc1
Reaction time: 0.75 h

Procedure:
A solution of N-chlorosuccinimide (2.92 g, 22 mmole) in 50 ml methylene chloride was added to a solution of 2,3-bis(4-methoxyphenyl)thiophene (5.92 g, 20 mmole) in 70 ml methylene chloride and 75 ml acetic acid. After 45 minutes at room temperature, the reaction mixture was heated at reflux for 18 hours. The cooled reaction mixture was then concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1.[C:18]([N:25]1[CH2:33][CH2:32][CH:28]([C:29](O)=[O:30])[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:29]([CH:28]2[CH2:32][CH2:33][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]2)=[O:30])=[N:6][CH:7]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 15 h
Yield: 17.9 %

Procedure:
To a stirred solution of N-(5-chloropyridin-2-yl)-2-aminobenzamide (0.5 g, 1.79 mol) and Boc-isonipecotic acid (0.41 g, 1.79 mmol) in N,N-dimethylformamide (30 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.69 g, 3.58 mmol). After stirring for 15 h, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water, and the layers separated. The organic phase was washed with saturated aqueous sodium chloride, dried (magnesium sulfate), filtered, and concentrated in vacuo. The solid was suspended in ether, sonicated, and filtered to give 0.147 g (18%) of a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Nc2cccc(C(F)(F)F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4cccc(C(F)(F)F)c4)C3)CC2)cc1
Yield: 23.1 %

Procedure:
The title compound (D165) (17 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-chloro-2-(3-((3-(trifluoromethyl)phenyl)amino)azetidin-1-yl)nicotinic acid (D115) (50 mg, 0.135 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (30.62 mg, 0.135 mmol).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH:18]([CH3:32])[C:19]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=3)([OH:24])[C:20]([F:23])([F:22])[F:21])[CH:12]=2)=[N:6][CH:5]=1.[Li+].[OH-].O>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:33])=[O:2])=[CH:5][N:6]=2)=[CH:12][C:13]=1[CH:18]([CH3:32])[C:19]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=1)([OH:24])[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1cc(Oc2ccc(C(=O)O)cn2)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
6-{4-Chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-nicotinic acid methyl ester (14 mg, obtained in Example 132) was dissolved in THF (5 mL). The mixture was cooled in an ice bath and aqueous LiOH solution (1.0 M, 0.048 mL) was added. The mixture was stirred over night at r.t. The reaction mixture was poured into water and extracted with ethyl acetate. The aqueous phase was acidified with 2 M aqueous HCl to pH 1 and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and the solvent was evaporated. The title compound was obtained as an off-white solid (12 mg, 88%) and was used without further purification. MS (neg. ion, m/e)=485.0 [(M−H)−].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11](=O)[O:10]1.O.[NH2:23][NH2:24]>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11](=[O:10])[NH:24][N:23]=1
Reactant: NN
Reactant: COc1ccc2c(c1)C(=O)OC2=Cc1c(Cl)cncc1Cl
Solvent: O
Solvent: CO
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[nH]c(=O)c2c1
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A suspension of 3-(3,5-dichloro-pyridin-4-ylmethylene)-6-methoxy-3H-isobenzofuran-1-one (84.4 g, 0.126 mole), prepared as described in example 37, in CH3OH (200 ml) under N2 was added with hydrazine monohydrate (18.4 ml, 0.378 mole). The mixture was refluxed for 1 hour, then left overnight at room temperature and cooled over ice. The solid was filtered, washed with cold CH3OH and dried in oven at 50° C. under vacuum; 33.3 g of the title compound were thus obtained (yield: 80%). m.p.: 259-262° C.