Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN[C:4]([C@H:6]1[O:10][C@@H:9]([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:5].C1([C@@]2(N3C4N=CN=C(N)C=4N=C3)O[C@H](CO)[C@@H](O)[C@H]2O)CCCCC1.[Mg+2].[Cl-].[Cl-]>C1(N2C=NC3C2=NC=NC=3N[C@H](CC2C=CC=CC=2)CO)C=CC=CC=1>[C@@H:9]1([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[O:10][C@H:6]([CH2:4][OH:5])[C@@H:7]([OH:22])[C@H:8]1[OH:21]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: Nc1ncnc2c1ncn2[C@]1(C2CCCCC2)O[C@H](CO)[C@@H](O)[C@H]1O
Agent: OC[C@@H](Cc1ccccc1)Nc1ncnc2c1ncn2-c1ccccc1
Agent: [Cl-]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 1 h

Procedure:
Incubation tubes, in triplicate, receive 100 μl of [3H]NECA (94 nM in the assay), 100 μl of 1 μM cyclohexyladenosine (CHA), 100 μl of 100 mM MgCl2, 100 μl of 1 IU/ml adenosine deaminase, 100 μl of test compounds at various concentrations over the range of 10-10M to 10-4M diluted with assay buffer (50 mM Tris-HCl pH 7.7) and 0.2 μl of membrane suspension (5 mg wet weight), in a final volume of 1 ml of 50 mM Tris-HCl pH 7.7. Incubations are carried out at 25° C. for 60 minutes. Each tube is filtered through GF/B glass fiber filters using a vacuum. The filters are rinsed two times with 5 ml of the ice-cold buffer. The membranes on the filters are transferred to scintillation vials to which 8 ml of Omnifluor with 5% Protosol is added. The filters are counted by liquid scintillation spectrometry.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[O:7])[CH2:3][CH2:2]1.[Cl-].[NH4+].C(O)C.CN(C)C=O>[Fe].O>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([C:6]([NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[O:7])[CH:13]=2)=[CH:16][CH:17]=1
Reactant: O=C(NCC1CC1)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc(C(=O)NCC3CC3)c2)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
After adding 0.35 g of 2-[(cyclopropylmethyl)aminocarbonyl]-4-(4-nitrophenoxy)pyridine to a mixture of 0.7 g of iron powder, 1.4 g of ammonium chloride, 10 ml of ethanol, 10 ml of dimethylformamide and 5 ml of water, the mixture was vigorously stirred at 100° C. for 20 minutes. The reaction solution was filtered with celite and the solvent was distilled off under reduced pressure to obtain 0.37 g of the target substance as a light brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl.Cl[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][N:11]1[CH2:10][CH2:9][O:8][C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]1=2
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCO2
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN1CCOc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.8 %

Procedure:
A solution of 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.0 g, 5.55 mmol) in anhydrous DMF (25 mL) under argon was cooled and treated portionwise with sodium hydride (0.677 g, 16.93 mmol) at 5-10° C. 2-chloro-N,N-dimethylethanamine hydrochloride (1.599 g, 11.10 mmol) was added portionwise at 5-10° C., and the resulting heterogeneous red-brown mixture was allowed to warm to room temperature. After 3 hours at room temperature, the mixture was heated to 90° C. and stirred for 30 minutes. The mixture was cooled to room temperature, quenched by the addition of water (25 mL), and diluted with EtOAc. A small amount of 1 N NaOH was added to basify the mixture to pH ˜9-10. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine (×2), dried (Na2SO4), filtered, and concentrated to afford a dark red oil. The material was purified on silica gel, eluting with 5% MeOH/CH2Cl2, to yield the title compound as a dark orange-red oil (458 mg, 32.8%). 1H NMR (DMSO-d6) δ 7.49-7.39 (m, 2H), 6.87-6.84 (m, 1H), 4.27-4.25 (m, 2H), 3.50-3.37 (m, 4H), 2.43 (t, 2H, J=6.7 Hz), 2.19 (s, 6H); ESI-MS (m/z, %): 252 (MH+, 100).
Reaction SMILES: [CH2:1]1[O:18][C:17]2[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br)=[CH:4][C:3]=2[O:2]1.[I-:19].[Na+]>CC(C)=O>[CH2:1]1[O:18][C:17]2[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][I:19])=[CH:4][C:3]=2[O:2]1
Reactant: [I-]
Reactant: BrCCCCCCCOc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCCCCOc1ccc2c(c1)OCO2

Procedure:
A mixture of 43.5 g. of 7-(3,4-methylenedioxyphenoxy)heptyl bromide, 20.7 g. of sodium iodide and 300 ml. of acetone was heated at reflux for 2 hours. The reaction mixture was filtered, the filtrate evaporated in vacuo, and the residue partitioned between water and methylene dichloride. The methylene dichloride layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue comprising 7-(3,4-methylenedioxyphenoxy)heptyl iodide was used without further purification in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14](O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1(N)CCCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(O)c1ccc(-c2cccc(Cl)c2)cc1
Solvent: NC1CCCCC1
Product: O=C(O)CCCc1ccc(-c2cccc(Cl)c2)cc1
Yield: 41 %

Procedure:
Prepared analogous to Example 9 from 4-(3'-chloro-4-biphenylyl)-4-hydroxy-butyric acid. Melting point of the cyclohexylamine salt: 147°-148° C. Yield: 41% of theory.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:23]2[CH2:26][C:25](=O)[CH2:24]2)=[CH:18][CH:17]=1.CC(C)([O-])C.[K+].CS(Cl)(=O)=O>O1CCCC1.C(OCC)C.O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)[N:23]2[CH2:26][C:25](=[CH:1][S:2]([CH2:5][C:6]3[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=3)(=[O:4])=[O:3])[CH2:24]2)=[CH:29][CH:30]=1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: COC(=O)c1ccc(CS(C)(=O)=O)s1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)s1
Temperature: -70 °C
Yield: 15.3 %

Procedure:
Methyl 5-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methylsulfonylmethyl)thien-2-yl-carboxylate may be obtained in the following manner: 5.15 g of methyl 5-(methylsulfonylmethyl)thien-2-ylcarboxylate are added, at room temperature under an argon atmosphere, to a solution of 6.12 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 200 cm3 of tetrahydrofuran and then the suspension obtained is cooled to −70° C. There are successively added 2.47 g of potassium tert-butoxide, and then after 1 hour 30 min at this temperature a solution of 1.7 cm3 of methylsulfonylchloride in 8 cm3 of ethyl ether over 2 minutes. The reaction medium is maintained for 1 hour at −70° C. and then the temperature is allowed to rise to around 20° C. before pouring in 80 cm3 of distilled water. The tetrahydrofuran is expelled under reduced pressure and the aqueous residue obtained is extracted with 500 cm3 of dichloromethane. The mixture is separated after settling, the organic phase is washed with 3 times 80 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. 1.6 g of methyl 5-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methylsulfonylmethyl)thien-2-ylcarboxylate are obtained in the form of a cream-colored foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH2:6][C:5]([CH2:9][N+:10]([O-])=O)([OH:8])[CH2:4][CH2:3]1.CO>[OH-].[Pd+2].[OH-]>[NH2:10][CH2:9][C:5]1([OH:8])[CH2:6][CH2:7][C:2]([CH3:1])([CH3:13])[CH2:3][CH2:4]1
Reactant: CC1(C)CCC(O)(C[N+](=O)[O-])CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(O)(CN)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4,4-dimethyl-1-(nitromethyl)cyclohexanol (1.5 g, 0.0072 mol) and palladium hydroxide (0.1 g, 0.0001 mol) in methanol (50 mL, 1 mol) was stirred under hydrogen (1 atm) at room temperature overnight. The mixture was filtered and concentrated to afford the desired product as a clear oil. (1.08 g, 95%).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH2:11][CH:12]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:13]1[C:21]2[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)(=O)=O>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:12]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:11][CH2:10][CH2:9][C:1]#[N:2])=[CH:26][CH:27]=1
Reactant: CSCc1cccc2c(C(CCCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
91.9 mg (1.41 mmol) of potassium cyanide were added to 309 mg (0.71 mmol) of the compound from Example 65A in 5 ml of DMF. The mixture was stirred at 80° C. for 2 h and then concentrated, and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). DMF was removed by taking the crude product up in dichloromethane, washing twice with water and saturated aqueous sodium chloride solution, drying over magnesium sulfate, filtering and concentrating. 134 mg (52% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:5][N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.Br[CH2:43][CH2:44][N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:18][CH2:19][N:20]([CH2:43][CH2:44][N:45]3[C:49](=[O:50])[C:48]4=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]4[C:46]3=[O:55])[CH2:21][CH2:22]2)=[CH:5][N:4]([C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(CCN4C(=O)c5ccccc5C4=O)CC3)c2c1
Yield: 57.6 %

Procedure:
A mixture of 80 mg 6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-piperazin-1-yl-quinoline obtained in Example 187, 46 mg N-(2-bromoethyl)phthalimide, 19 mg sodium carbonate, and 8 mL acetonitrile was heated overnight under reflux. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 61 mg of the title compound as a colorless amorphous.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C@@H:25]([NH2:27])[CH3:26]>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C@@H:25]([NH:27][CH2:16][CH2:15][C:2]1([OH:1])[CH2:3][CH2:4][C:5]2([O:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH2:9][O:10]2)[CH2:13][CH2:14]1)[CH3:26]
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: C[C@H](N)c1ccccc1Cl
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccccc1Cl
Yield: 89 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(2-chloro-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 89% of theory; LC (method 8): tR=1.18 min; Mass spectrum (ESI+): m/z=382/384 (Cl) [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]2=[O:19])=[N:5][N:4]=1.[CH3:20][N:21]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:22](Cl)=[O:23].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:22](=[O:23])[N:21]([CH3:20])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]2=[O:19])=[N:5][N:4]=1
Reactant: C=CCCN1CCC(O)N(c2nnc(OC)s2)C1=O
Reactant: CN(C(=O)Cl)C1CCCCC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CCCN1CCC(OC(=O)N(C)C2CCCCC2)N(c2nnc(OC)s2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-but-3-enyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N-methyl-N-cyclohexylcarbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrytallized to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-but-3-enyl-6-(N-methyl-N-cyclohexylcarbamoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CCCP(=O)=O.C(OCC)(=O)C.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:18]1([C:16]2[N:17]=[C:12]3[CH:11]=[CH:10][C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[O:24])=[CH:14][N:13]3[N:15]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3ccccc3)nn2c1
Reactant: C1CCNC1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccc2nc(-c3ccccc3)nn2c1
Yield: 35.1 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (112 mg, 309 μmol), pyrrolidine (220 mg, 256 μl, 3.09 mmol), propylphosphonic anhydride in ethyl acetate 50% (492 mg, 455 μl, 773 μmol) and N,N-diisopropylethylamine (120 mg, 158 μl, 927 μmol) in tetrahydrofuran (7.00 ml) was refluxed for 18 hours. The solvent was evaporated, the residue was triturated with saturated aqueous sodium hydrogencarbonate. The precipitated solid was filtered off, washed with water and dried in vacuo, affording 2-methyl-4-(pyrrolidine-1-carbonyl)-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-amide (45 mg, 35%) as brown solid. Mp.: 210° C. MS: m/z=416.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8](O)=[O:9])=O.O.[NH2:17][NH2:18]>>[Cl:1][C:2]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]1[CH2:6][CH2:7][C:8](=[O:9])[NH:17][N:18]=1
Reactant: O=C(O)CCC(=O)c1cccc(O)c1Cl
Reactant: NN
Solvent: O
Product: O=C1CCC(c2cccc(O)c2Cl)=NN1

Procedure:
3-(2-chloro-3-hydroxybenzoyl)propionic acid was cyclised with hydrazine hydrate in a similar manner to that described in Example 3(i) to give 6-(2-chloro-3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15](O)=[O:16])(=[O:10])=[O:9])=[C:4]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.[N:36]1([CH2:41][CH2:42][NH2:43])[CH2:40][CH2:39][CH2:38][CH2:37]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([NH:43][CH2:42][CH2:41][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:16])(=[O:10])=[O:9])=[C:4]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:33])[F:34])[CH:26]=2)(=[O:23])=[O:24])[CH:3]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)c2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: NCCN1CCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCCN1CCCC1)c1cccc(CS(=O)(=O)c2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 37.2 %

Procedure:
Following General Procedure R, the title compound (21 mg, 49%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoic acid (48 mg, 0.085 mmol), 2-(pyrrolidin-1-yl)ethanamine (16 μl, 0.13 mmol), EDC (32 mg, 0.17 mmol) and DMAP (cat.) in DMF (2 ml).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]4[CH:37]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:40][N:39]=[N:38][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]4[CH:37]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][CH2:13][OH:14])[CH:2]=1.[C:15]([O:22]C(OC(C)(C)C)=O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[OH-].[Na+].C(OCC)(=O)C.CCCCCCC>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][CH2:13][OH:14])[CH:2]=1.[C:15](=[O:16])([O-:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: OCC=Cc1cnc2ccccc2c1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[O-]

Procedure:
To a 500-mL three-necked round-bottom flask equipped with an overhead mechanical stirrer was charged 3-(3-quinolyl)-2-propen-1-ol (13.03 g, 70.43 mmol) as a mixture of cis- and trans- isomers (81% cis, and 19% trans), di-tert butyl dicarbonate (16.91 g, 77.48 mmol, 1.11 equiv), tetra n-butylammonium hydrogen sulfate (742 mg, 2.17 mmol) and methylene chloride (135 mL). The stirred mixture which resulted was cooled to 0 to 5° C. at which time aqueous 25% sodium hydroxide (33.3 mL) was added over 45 minutes such that the internal temperature did not rise above 20° C. Upon completion of the reaction (1 to 4 hours) as indicated by TLC (3:2 ethyl acetate/heptane), the reaction mixture was diluted with methylene chloride (50 mL) and washed with water (2×125 mL). The organic was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide the 3-(3-quinolyl)-2-propen-1-ol-t-butyl carbonate: 18.35g, 91.4% as an oil. This material can be further purified to remove lower Rf impurities by eluting through a plug of silica gel with heptane/acetone/triethylamine (9:1:0.1). The product eluant is then concentrated under reduced pressure and further dried by the azeodistillation of ethyl acetate. This procedure provides the purified carbonate as a colorless oil which retains the original ratio of cis and trans isomers: 17.50 g, 87.2%.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:20]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:26]([O:28]C)=[O:27])[CH:17]=4)[N:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O.O1CCCC1>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:20]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:26]([OH:28])=[O:27])[CH:17]=4)[N:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)CCCO4)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of methyl 2-(chroman-6-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (130 mg, 0.33 mmol) in water (1 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (53 mg, 1.33 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted to pH 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(chroman-6-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (80 mg, 61%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[O:8]C.Br>O>[F:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[OH:8]
Reactant: COc1c(F)cc(C(C)=O)cc1F
Agent: Br
Solvent: O
Product: CC(=O)c1cc(F)c(O)c(F)c1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A mixture of 1-(3,5-difluoro-4-methoxyphenyl)ethanone (12 g, 64.5 mmol) and 48% aqueous HBr (32 mL) was stirred at reflux for 30 h. The reaction was cooled to rt and diluted with water and the aqueous layer was extracted twice with methylene chloride. The combined organics were dried (Na2SO4), filtered, and concentrated to give 1-(3,5-difluoro-4-hydroxyphenyl)ethanone (10 g, 91%), mp 141-143° C.; MS m/z 171 (M−H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:15](OCC)(OCC)(OCC)[CH3:16]>>[CH3:15][C:16]1[N:4]2[CH:5]=[CH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1cc(-c2ccccn2)ccn1
Product: Cc1nnc2cc(-c3ccccn3)ccn12

Procedure:
A mixture of 2.0 g of 2'-hydrazino-2,4'-bipyridine and 50 ml of triethyl orthoacetate was heated on a steam bath for 18 hours, then chilled, filtered and the crystals washed with hexane. These crystals were recrystallized from methylene chloride, giving 1.8 g of the desired product as white crystals, mp 239°-241° C.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[O:25][N:24]=[C:23]([Br:26])[CH:22]=1.N(OC(C)(C)C)=O>O1CCCC1>[Br:26][C:23]1[CH:22]=[C:21]([C:3]2[C:4]([C:19]#[N:20])=[N:5][N:6]([C:7]3[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=3[Cl:18])[CH:2]=2)[O:25][N:24]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cc(Br)no1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1cc(Br)no1
Temperature: 65 °C

Procedure:
To a solution of 5-amino-4-(3-bromoisoxazol-5-yl)-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.1 g) in tetrahydrofuran (1.5 ml) was added t-butyl nitrite (77 μl). The mixture was heated to 65° C. for 1 hour, then cooled and evaporated. The residue was taken up in t-butanol and freeze dried to give the title compound as a pale yellow solid, m.p. 145° C.