Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:20](O)=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O.[CH2:36]([NH:38][CH:39]([CH3:41])[CH3:40])[CH3:37]>O1CCCC1>[CH2:36]([N:38]([CH:39]([CH3:41])[CH3:40])[C:20]([C:12]1[N:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:19]2[C:14]([CH:13]=1)=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:21])[CH3:37]
Reactant: COc1ccc(-n2c(C(=O)O)cc3ccccc32)cc1OC
Reactant: CCNC(C)C
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(C(=O)c1cc2ccccc2n1-c1ccc(OC)c(OC)c1)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(3,4-Dimethoxyphenyl)indole-2-carboxylic acid (2.0 g, 6.8 mmol) was stirred in tetrahydrofuran (10 ml). Triethylamine (1 ml, 7.5 mmol) was added and the mixture was cooled to 0° C. Ethyl chloroformate (0.7 ml, 7 mmol) was added dropwise, followed by stirring for 30 minutes. N-ethyl isopropylamine (0.6 g, 7 mmol) in tetrahydrofuran was added, followed by stirring for 30 minutes and refluxing for 6 hours. The tetrahydrofuran was evaporated in vacuo, and the residue was dissolved in toluene. The toluene solution was washed with water, dried, evaporated in vacuo, applied onto a flash chromatography column (silica gel, 30 g) and eluted with toluene/acetone (9.5:0.5). The desired fractions were concentrated and the residue triturated with diisopropyl ether to give 1-(3,4-dimethoxyphenyl)indole-2-carboxylic acid N-ethyl isopropyl amide as white crystals which were then filtered and dried. Yield: 50 mg (2% of theoretical). Rf : 0.53 (toluene/acetone 7:3). The H-NMR spectra was consistent with the assigned structure.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.[C:7]([C:12]1[C:13](=[O:25])[CH2:14][CH:15]([CH:19]2[CH2:24][CH2:23][CH2:22][S:21][CH2:20]2)CC=1O)(=[O:11])[CH2:8][CH2:9][CH3:10]>C(OC)(C)(C)C>[C:7]([C:12]1[C:13](=[O:25])[CH2:14][CH:15]([CH:19]2[CH2:24][CH2:23][CH2:22][S:21][CH2:20]2)[CH2:2][C:1]=1[Cl:6])(=[O:11])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=O)C1=C(O)CC(C2CCCSC2)CC1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: COC(C)(C)C
Product: CCCC(=O)C1=C(Cl)CC(C2CCCSC2)CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
420 ml of oxalyl chloride were added at 0° to 5° C. to 141.2 g (0.5 mol) of 2-butyryl-3-hydroxy-5-(tetrahydrothiopyran-3-yl)cyclohex-2-en-1-one, and the mixture was stirred at room temperature for 16 hours and concentrated. The oil obtained was treated with methyl tert.-butyl ether, and the resulting solid was filtered off with suction and dried. This gave 125.9 g (84% yield) of 2-butyryl-3-chloro-5-(tetrahydrothiopyran-3-yl)cyclohex-2-en-1-one having a melting point of 97° C. (decomposition) (compound no. 312).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][C:14]([CH3:19])([CH3:18])[C:15]([CH3:17])=[CH:16][C:11]=2[CH:10]=1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C=O>[Si:27]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][C:14]([CH3:18])([CH3:19])[C:15]([CH3:17])=[CH:16][C:11]=2[CH:10]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC1=Cc2cc(Sc3ccccc3O)ccc2OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1=Cc2cc(Sc3ccccc3O[Si](C)(C)C(C)(C)C)ccc2OC1(C)C
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
6-(2-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (1.1 g) (see Preparation 10) was dissolved in dry dimethylformamide (2 ml) and imidazole (0.55 g) and tert-butyidimethylsilyl chloride (0.61 g) were added. The flask was fitted with a calcium chloride drying tube and the mixture stirred at 40° C for 90 minutes. Water was added and the mixture was extracted with diethyl ether. The organic extract was washed with aqueous sodium hydrogen carbonate solution (×2), dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the crude product was chromatographed on silica using 4:1 hexane:dichloromethane as the eluent to yield 6-(2-tert-butyldimethylsilyloxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (1.43 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=2)[N:3]=1.C(O)(=O)C.[BH4-].[Na+].O>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=2)[N:3]=1
Reactant: Cc1cccc(OCc2ccc(/C=C/[N+](=O)[O-])cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Cc1cccc(OCc2ccc(CC[N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
To a solution of 2-methyl-6-(4-((E)-2-nitro-vinyl)-benzyloxy)-pyridine (5.00 g, 18.5 mmol) described in Manufacturing Example 3-1-3 and acetic acid (5 mL) in dimethyl sulfoxide (50 mL) was added sodium borohydride (1.2 g, 29.6 mmol) under nitrogen atmosphere at room temperature while cooling appropriately, which was stirred for 10 minutes at room temperature. Water was then added dropwise. The mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:5 then 1:2) to obtain the title compound (2.8 g, 56%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]([NH2:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH:11]([NH:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a cold solution of 2-fluoro-nitrobenzene (31.8 g, 0.225 mol) in ethanol (300 mL) cooled in an ice bath was added isopropylamine (54.0 mL, 0.634 mol), followed by the addition of a solution of potassium carbonate (31.1 g, 0.225 mol) in water (120 mL). The mixture was stirred at 0° C. for 1 h, then refluxed for 6 h. The reaction was terminated by cooling the mixture to ambient temperature, and evaporating it under reduced pressure yielding an orange residue. The residue was partitioned between ethyl ether (800 mL) and a brine solution (300 mL). The organic layer was dried and filtered, to provide the title intermediate (39 g) as an orange liquid. 1H-NMR (CDCl3, 300 MHz): δ (ppm) 8.06 (d, 1H), 7.30 (t, 1H), 6.74 (d, 1H), 6.48 (t, 1H), 3.73 (hept, 1H), 1.20 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(I)cc1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(I)ccc1CBr
Temperature: 25 °C
Yield: 57.2 %

Procedure:
To a solution of 2-fluoro-4-iodotoluene (2.83 g, 12 mmol) in CCl4 (120 mL) were added NBS (2.24 g, 12.6 mmol) and BPO (0.06 g, 0.24 mmol). The reaction mixture was refluxed for 9 h under N2, then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE) to give the title compound as a white solid (2.16 g, 57%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2>CC1C=CC(C(C)C)=CC=1.CC1C=CC(S([N-][C@@H]([C@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.Cl[Ru+].CCN(CC)CC>[OH:1][C@@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: N#Cc1cccc2c1CCCC2=O
Agent: Cl[Ru+]
Agent: Cc1ccc(S(=O)(=O)[N-][C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CCN(CC)CC
Product: N#Cc1cccc2c1CCC[C@H]2O
Temperature: 30 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a stirred solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-1 (3.0 g, 17.5 mmol) in 5:1 HCO2:NEt3 (24 mL) was added RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.13 g, 0.26 mmol). The mixture was stirred at 30° C. for 15 h then partitioned between EA and H2O. The combined organic layers were dried over Na2SO4 and chromatographed (EA/hex) to provide 2.99 g (99%) of (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-2 as a white solid. LCMS-ESI (m/z) calculated for C11H11NO: 173.2; found 174.1 [M+H]+, 156.1 [M−NH4]+, tR=2.60 min. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=7.8 Hz, 1H), 7.54 (dt, J=8.7, 4.4 Hz, 1H), 7.34-7.26 (m, 1H), 4.85-4.71 (m, 2H), 3.48 (s, 1H), 3.13-2.96 (m, 1H), 2.90 (ddd, J=17.7, 7.8, 5.6 Hz, 1H), 2.15-1.95 (m, 2H), 1.97-1.76 (m, 2H). Chiral HPLC: (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile was eluted with 5% IPA/hexane: 99.1% ee, tR=15.3 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg][Cl:21])(C)C.[O:22]1[CH2:26]CCC1>>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:26]([Cl:21])=[O:22])=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Mg]Cl
Reactant: FC(F)(F)c1ccn(-c2ncccc2Cl)n1
Reactant: C1CCOC1
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: -5 °C
Yield: 84.6 %

Procedure:
In a reaction vessel equipped with a thermometer, septum, nitrogen inlet and stirring bar, 500 mg (2.02 mmol) of 1-(3-chloro-2-pyridyl)-3-trifloromethyl-1H-pyrazole were dissolved in 3 ml of dry tetrahydrofurane. By means of a syringe, 2.0 ml of a 2 M solution of isopropyl magnesium chloride in tetrahydrofurane were added dropwise with stirring, while cooling the vessel with an ice bath and keeping the internal temperature at about 20° C. The ice bath was removed and the mixture was stirred for further 20 minutes at 23° C. Then the mixture was cooled again to −5° C. and 4.25 ml of a 20% (w/w) solution of phosgene in toluene were added dropwise with stirring. The mixture was allowed to war at 23° C. and stirred for further 1 h at 23° C. The thus obtained reaction mixture was evaporated to dryness, redissolved in toluene and stirred for further 30 min. at 50° C. Solids were removed by filtration and washed with toluene. The combined filtrates were evaporated to dryness to yield 0.53 g of the title compound with a purity>85% (yield 84.6%).
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:19][N+](C)(C)C)=[CH:15][NH:16]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C-:24]#[N:25].[Na+]>CCO>[CH2:2]([O:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:19][C:24]#[N:25])=[CH:15][NH:16]2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [C-]#N
Reactant: C[N+](C)(C)Cc1c[nH]c2cc(OCc3ccccc3)ccc12
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: N#CCc1c[nH]c2cc(OCc3ccccc3)ccc12
Yield: 95.3 %

Procedure:
A mixture of (6-benzyloxy-1H-indol-3-ylmethyl)-trimethylammonium iodide (2.2 g, 5 mmol), sodium cyanide (500 mg, 10.2 mmol), and 95% EtOH (50 mL) was refluxed under nitrogen for 5 hours. The solvent was removed in vacuo, and the residue was taken in DCM, and washed with water, then dried with sodium sulfate, and evaporated in vacuo to afford a white solid, which was recrystallized from EtOH to give (6-benzyloxy-1H-indol-3-yl)-acetonitrile (1.25 g, 86%). MS (ES): 263 (MH+).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[CH3:28])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O>[CH3:28][C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:22]=[CH:23][C:18]=1[C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:32][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)cc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1C
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 55.1 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (6.28 g, 15.12 mmol) was dissolved in MeOH (60 mL) and cooled to −40° C. 3.8 M NaOH (3.98 mL, 15.12 mmol) was dissolved in water (6 mL) and added to the mixture and the reaction stirred at −40° C. for 40 min. Hydroxylamine (50% by weight in water, 0.926 mL, 15.12 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a preheated 80° C. warm solution of 6 M HCl (76 mL, 453.53 mmol) and stirred for 20 min. The reaction mixture was partitioned between water and DCM. The aqueous phase was extracted twice with DCM and the combined organic phase was dried and evaporated. The compound was purified in two runs by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 35-75% acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (3.2 g, 55%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.81-1.93 (m, 2H), 2.21-2.42 (m, 2H), 2.44 (s, 3H), 3.03-3.13 (m, 1H), 3.59 (s, 3H), 3.63-3.75 (m, 1H), 4.12-4.20 (m, 1H), 5.02 (dd, 1H), 5.65 (s, 1H), 7.30 (d, 1H), 7.37-7.44 (m, 2H). MS m/z 383 (M−H)−
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=3)[CH2:23][C:22](=[O:34])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C2=Nc3ccc(-c4ccccc4F)cc3NC(=O)C2)ccn1

Procedure:
Prepared from {3-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K64) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a green solid (40 mg).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][CH:6]=[C:5]3[O:4][C:3]2[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:2]=2[F:1])=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: Nc1cccc2c(Oc3cc(C(F)(F)F)ccc3F)ccnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cc(C(F)(F)F)ccc4F)ccnc23)c1F
Yield: 43.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(2-fluoro-5-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-35, 100 mg, 0.31 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 133 mg, 0.46 mmol), oxalyl chloride (187 mg, 0.69 mmol), DMF (1 drop) and DIPEA (120 mg, 0.93 mmol) in CH2Cl2 (4 mL) to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.74 (s, 1H), 8.78 (d, J=7.8 Hz, 1H), 8.70 (d, J=5.4 Hz, 1H), 8.11-8.05 (m, 3H), 7.83-7.71 (m, 3H), 7.41-7.30 (m, 2H), 6.83 (d, J=4.8 Hz, 1H), 4.29 (d, J=5.4 Hz, 2H), 1.12 (s, 9H); MS (m/z): 592.33 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.ClC(O[C:47]1[CH:52]=[CH:51]C=[CH:49][CH:48]=1)=O>ClCCl>[C:32]1([C:35]2[CH:51]=[CH:52][CH:47]=[CH:48][CH:49]=2)[CH:33]=[CH:34][C:29]([S:26]([NH:25][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:13]3[C:6]4=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]4[N:4]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:24])(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a stirred solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9 of Example 1, 1.55 g, 5.3 mmol) and triethylamine (0.80 mL, 5.8 mmol) in dichloromethane (26 mL) cooled in an ice bath was added dropwise phenyl chloroformate (0.69 mL, 5.5 mmol), and the mixture was stirred at ambient temperature. After 30 min, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate (30 mL) and dichloromethane (30 mL). The organic layer was separated and the aqueous phase was extracted with dichloromethane (30 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was recrystallized from dichloromethane/hexane to give 1.90 g (87%) of the title compound as pale brown crystals: 1H-NMR (CDCl3) δ 7.43-7.11 (9H, m), 6.91 (1H, s), 5.50 (1H, br.s), 3.57 (2H, pseudo q, J=6.9 Hz), 2.98 (2H, t, J=6.9 Hz), 2.83 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.52 (3H, s), 1.28 (3H, t, J=7.6 Hz).
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.[Cl:23][C:24]1[CH:32]=[N:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](O)=[O:27].ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[Cl:23][C:24]1[CH:32]=[N:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1)=[O:27]
Reactant: NCc1ccc(CCO)cc1
Reactant: O=C(O)c1c(Cl)cncc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1ccc(CCO)cc1)c1c(Cl)cncc1Cl
Yield: 44.1 %

Procedure:
Using the EDCI coupling general procedure F: Reaction of 2-(4-Aminomethyl-phenyl)-ethanol (306 mg, 2.03 mmol), 3,5-dichloroisonicotinic acid (385 mg, 2.03 mmol), 1-hydroxybenzotriazole (301 mg, 2.22 mmol), 4-methyl morpholine (0.50 mL, 4.45 mmol), and EDCI (426 mg, 2.22 mmol) in anhydrous DMF (5 mL) overnight at room temperature and overnight at 40° C. followed by column chromatography on silica gel (2:2:96 MeOH—NH4OH—CH2Cl2) gave the title compound (291 mg, 44%) as a white foam.
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.Cl.[CH2:15]([O:17][C:18](=[O:28])[C@H:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[NH2:20])[CH3:16].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.CO>[N+:11]([C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH:20][C@H:19]([C:18]([O:17][CH2:15][CH3:16])=[O:28])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:6])=[C:2]([Cl:1])[CH:10]=1)([O-:13])=[O:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1Cl)C(=O)OCC
Reaction time: 0.25 h

Procedure:
A solution of 2-chloro-4-nitrobenzoic acid (10.0 g, 49.6 mmoles), (L)-glutamate diethyl ester hydrochloride (11.9 g, 49.6 mmoles), and 1-hydroxybenzotriazole (6.7 g, 49.6 mmoles) in dry dimethylformamide (2150 mL) was stirred under nitrogen while triethylamine (5.02 g, 6.92 mL, 49.6 mmoles) was added dropwise during 1 minute. After 15 minutes, 1,3-dicyclohexylcarbodiimide (11.3 g, 54.6 mmoles) was added in portions during 1 minute. The reaction mixture was filtered after 18 hours and the solids were rinsed with dichloromethane (2×50 mL). The filtrate was spin evaporated (high vacuum) to an amber residue that was dissolved in dichloromethane (300 mL). The organic phase was washed successively with saturated bicarbonate, 5% citric acid, and brine solution (1×300 mL each). The organic phase was then dried (MgSO4), filtered, and poured onto a silica gel column (500 g, pre-wet with dichloromethane). The column was rinsed with dichloromethane (500 mL), followed by gradient elution of the product with 10% and 15% added ethyl acetate (8×250 mL fractions each). Like fractions were combined by spin evaporation and dried to give a white solid; yield, 9.8 g (51%); mp 95°-96° C.; 1H-NMR (DMSO-d6) δ 1.17 and 1.21 (2t overlapped, 6H), 1.8-2.2 (m, 2H), 2.46 (t obscured by DMSO, 2H), 4.0-4.2 (2 q overlapped, 4H), 4.46 (m, 1H), 7.68 (d, Jo =8 Hz, 1H), 8.25 (dxd, Jo =8 Hz, Jm =2 Hz, 1H), 8.34 (d, Jm 2 Hz, 1H), 9.14 (d, 1H); uv (MeOH) 260 nm max (9930), 236 min (6180), 205 max (25600); mass spec (CI) m/e 387 (100%), 341 (40), 184 (21).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH3:16])(=[O:3])[CH3:2].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:36])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:6]([CH3:16])=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=1[CH2:15][Br:36])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)c(OC(C)=O)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(C)c(OC(C)=O)c(CBr)c1
Temperature: 25 °C

Procedure:
A solution of methyl 4-acetoxy-3,5-dimethylbenzoate (2.4 g) in carbon tetrachloride (35 mL) was treated with AIBN (azobisisobutrylnitrile, 0.177 g, 0.1 equivalent) and NBS (N-bromosuccinimide, 2.117 g, 1.1 equivalents). The reaction was heated at reflux under a nitrogen atmosphere for 6 h. The reaction was cooled to room temperature and diluted with chloroform (30 mL). This solution was washed with water (4×50 mL) and then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. An off-white, waxy solid was recovered. Yield=4.63 g. The crude bromide was used as such for the following reaction.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][C:15]#[N:16].[H-].[Na+].[H][H].[CH3:21]I>CN(C)C=O>[CH3:21][CH:14]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][C:13]=2[CH:1]=1)[C:15]#[N:16]
Reactant: N#CCc1ccc2c(c1)Cc1ccccc1-2
Reactant: [H][H]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)c1ccc2c(c1)Cc1ccccc1-2

Procedure:
A solution of fluorene-2-acetonitrile (2g.) in dimethylformamide is treated with sodium hydride (415mg.) portionwise while stirring under nitrogen. After the evolution of hydrogen has ceased, the mixture is cooled to 10°-15° and treated dropwise with methyl iodide (2.82g.) in dimethylformamide (10ml.). After stirring for 30 minutes, the ice bath is removed and the mixture stirred at room temperature overnight. The reaction mixture is then poured into ice water and extracted with ether. The ether extracts are washed with water, dried (MgSO4) and evaporated to give the title compound.