Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:4][NH:3]1.CCN=C=NCCCN(C)C.Cl.[CH:28]1([C:32]2[C:40]([C:41]3[NH:45][C:44]([CH2:46][CH3:47])=[N:43][N:42]=3)=[CH:39][C:35]([C:36](O)=[O:37])=[C:34]([CH3:48])[CH:33]=2)[CH2:31][CH2:30][CH2:29]1>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:28]1([C:32]2[C:40]([C:41]3[NH:45][C:44]([CH2:46][CH3:47])=[N:43][N:42]=3)=[CH:39][C:35]([C:36]([N:3]3[CH2:4][CH2:5][CH:6]([C:8]4[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=4)[CH2:7][CH:2]3[CH3:1])=[O:37])=[C:34]([CH3:48])[CH:33]=2)[CH2:29][CH2:30][CH2:31]1
Reactant: CCc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Reactant: CC1CC(c2ccc(C#N)cc2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3C)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.9 %

Procedure:
To a round-bottom flask was added a solution of 4-(2-methylpiperidin-4-yl)benzonitrile (compound 176.3, 210 mg, 0.940 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (2 mL). EDC.HCl (404 mg, 2.11 mmol, 2.00 equiv), 4-dimethylaminopyridine (257 mg, 2.10 mmol, 2.00 equiv), and 4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 176.4, 300 mg, 1.05 mmol, 1.00 equiv) were added to the reaction mixture. The resulting solution was stirred for 4 h at 25° C., then diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 2×30 mL of NH4Cl (aq., sat.) and 2×30 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using silica gel column chromatography with dichloromethane/methanol (20:1) as eluent. The crude product (˜20 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (48% CH3CN up to 49% in 8 min, up to 100% in 3 min, down to 48% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 3.8 mg (1%) of the title compound as a white solid. m/z (ES+) 468 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH2:4][NH:3]1.[ClH:23].CC[O:26]C(C)=O>>[OH2:26].[ClH:23].[CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CCOC(C)=O
Agent: CC1CC(c2ncc3nc(-c4ccccn4)cc-3[nH]2)CCN1
Agent: Cl
Product: O

Procedure:
Using the method described in Example 30 by employing 2-(1-pyrrolidinylvinyl)-2-pyridine (freshly prepared before use) (2.20 g, 12.6 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (2.61 g, 12.6 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (2.2 mL, 12.6 mmol), piperidine (2.0 mL, 20.2 mmol), NEt3 (Aldrich Chemical Company) (2.0 mL) and SnCl2 (Aldrich Chemical Company) (38 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 650 mg (18%) of the free base as a beige colored solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.66 (s, 6), 2.42 (s, 3), 3.74 (s, 4), 7.01 (br s, 1), 7.37 (br s, 1), 7.90 (br s, 1), 8.08 (d, 1, J=7.9), 8.67 (br s, 1), 11.18 (s, 1). MS m/z: 294 (M+1). To a solution of 2-methyl-4-piperidyl-6-(2-pyridyl)pyrrolo[3,2-d]pyrimidine (0.65 g, 2.22 mmol) in EtOAc (30 mL) was added 1N etheral HCl (Aldrich Chemical Company) (2.20 mL, 2.22 mmol). The precipitate was collected by filtration, washed with EtOAc (2×10 mL), ether (3×15 mL) and dried under vacuum to give 621 mg (85%) of the title compound as a brown colored solid. Mp:>280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.72 (s, 6), 2.58 (s, 3), 4.06 (br s, 4), 7.16 (s, 1), 7.51 (dd, 1, J=7.4, 7.4), 8.01 (dt, 1, J=1.4, 7.6), 8.24 (d, 1, J=7.9), 8.76 (d, 1, J=4.4), 12.19 (s, 1), 14.36 (s, 1). MS m/z: 294 (M+1). Anal. Calcd. for C17H19N5.1.2HCl.0.4H2O: C, 59.18; H, 6.14; N, 20.30; Cl, 12.53. Found C, 59.23; H, 6.14; N, 20.03; Cl, 12.56.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[S:17]1[C:21]2[C:22]([C:26](Cl)=[O:27])=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.Cl>C(Cl)Cl>[C:1]1([S:7]([NH:10][C:26]([C:22]2[C:21]3[S:17][N:18]=[N:19][C:20]=3[CH:25]=[CH:24][CH:23]=2)=[O:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc2nnsc12
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc2nnsc12
Reaction time: 8 h

Procedure:
3.2 g of benzenesulfonamide are introduced at from 0°-5° C. into 50 ml of abs. pyridine and, while stirring at that temperature, a solution of 3.9 g of benzo-1,2,3-thiadiazole-7-carboxylic acid chloride in20 ml of methylene chloride is added dropwise. The mixture is stirred overnight and then poured onto ice-water, rendered slightly acidic with hydrochloric acid and extracted with methylene chloride, and the extracts are washed with water, dried and concentrated by evaporation. The residue is dissolved warm in tetrahydrofuran, treated with some silica gel, filtered, concentrated by evaporation and then recrystallised from tetrahydrofuran/hexane. The title compound resulting melts at 231°-233° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[CH:53]=[C:52]([C:54]2[CH:55]=[C:56]([NH2:60])[CH:57]=[CH:58][CH:59]=2)[CH:51]=[N:50]1>CN(C=O)C>[NH:49]1[CH:53]=[C:52]([C:54]2[CH:55]=[C:56]([NH:60][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:57]=[CH:58][CH:59]=2)[CH:51]=[N:50]1
Reactant: Nc1cccc(-c2cn[nH]c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn[nH]c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 8.9 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-pyrazol-4-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.002 g of product in 11% yield: LCMS (ESI) m/z 348 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.C(N(C(C)C)C(C)C)C.[C:48]([Si:50]([CH3:53])([CH3:52])[CH3:51])#[CH:49]>CN(C=O)C.[Cu]I>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:49]#[C:48][Si:50]([CH3:53])([CH3:52])[CH3:51])=[CH:10][CH:9]=2)[C:5]([C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:26][CH2:27]4)[CH:20]=[N:19][CH:18]=2)=[N:6]1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C#C[Si](C)(C)C)cc34)n2)C1
Temperature: 160 °C
Yield: 99.9 %

Procedure:
A mixture of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (579 mg, 0.991 mmol), copper(I) iodide (37.7 mg, 0.198 mmol), PdCl2(Amphos) (70.1 mg, 0.099 mmol), N-ethyl-N-isopropylpropan-2-amine (530 μL, 2.97 mmol), and ethynyltrimethylsilane (208 μL, 1.486 mmol) in DMF (9906 μL) was heated in the microwave for 15 min at 160° C. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% hexanes to 20% EtOAc/hexanes to give (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilyl)ethynyl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (596 mg, 0.990 mmol, 100% yield) as a yellow foam. MS (ESI, pos. ion) m/z: 602.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]3=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[C:5](=[O:25])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:3]=1.[CH3:34][N:35]=[C:36]=[O:37]>ClCCCl>[CH2:12]([O:11][C:10]1[C:6]2[C:5](=[O:25])[N:4]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:3]=[C:2]([NH:1][C:36]([NH:35][CH3:34])=[O:37])[C:7]=2[N:8]2[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]=12)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN=C=O
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(N)c32)C1=O
Solvent: ClCCCl
Product: CNC(=O)Nc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 4-amino-2-(4-fluorobenzyl)-10-benzyloxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (75 mg, 168 μmol) and methylisocyanate (24 mg, 419 μmol) in anhydrous 1,2-dichloroethane (3 mL) was heated in a sealed tube in an oil bath at 100° C. overnight. The product mixture was concentrated under vacuum. The intermediate dicarbonimidic diamide was dissolved in methanol, treated with an aqueous solution of KOH (0.1 mL, 2 M), and stirred at room temperature for one hour, and concentrated under vacuum. The residue was partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound. ES MS M+1=505
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:14]2[S:10][C:11](=[O:16])[NH:12][C:13]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(Cl)cc2)S1

Procedure:
A solution of 4-chloro-benzaldehyde (3 mmoles), thiazolidine-2,4-dione (3 mmoles) and piperidine (3 mmoles) in ethanol is heated at reflux overnight.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:28]I>CN(C)C=O.C(OCC)(=O)C>[CH3:28][N:23]([CH2:22][C:13]1([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:12][CH2:11][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:15][CH2:14]1)[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(C)(=O)=O)(C2CCCCC2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CC1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.28 h
Yield: 72.2 %

Procedure:
A 10-mL, round-bottomed flask was purged with nitrogen and then charged with a 60% sodium hydride dispersion in mineral oil (0.005 g, 0.125 mmol), and the flask was cooled at 0° C. in an ice-water bath. A solution of the sulfonamide from Step B (0.040 g, 0.107 mmol) in 0.8 mL of dimethylformamide was then added dropwise via syringe. The resulting mixture was stirred at 0° C. for 17 min, warmed to room temperature, and stirred for 10 min. The resulting thick mixture was then charged with methyl iodide (0.033 mL, 0.535 mmol), and the clear mixture was then stirred at room temperature for 5 days. The reaction mixture was then diluted with ethyl acetate and washed with two portions of 1 N HCl solution, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to give the title compound (0.030 g) as a light yellow oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C:13]([O:14][CH3:15])=N[C@H](C(C)C)C(OC)=[N:9]1)=[N+:2]=[N-:3].Cl.[OH2:22].N>O1CCOCC1>[NH2:9][C@@H:8]([CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[C:13]([O:14][CH3:15])=[O:22]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCCCN=[N+]=[N-]
Reactant: O
Agent: Cl
Agent: N
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CCCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Azido-4-[(2R,5S)-3,6-dimethoxy-2-isopropyl-2,5-dihydro-5-pyrazinyl]butane (2.17 g, 7.72 mmol) was dissolved in 30 ml dioxane and a solution of 1.28 ml conc. HCl in 30 ml water (15.45 mmol) was added dropwise, the mixture stirred under argon at ambient temperature overnight. Ammonia solution was added until pH 9 was reached, the solution extracted with chloroform, dried (MgSO4), and the valine methyl ester was removed by bulb-to-bulb distillation (0.05 torr, 25° C.).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][N:42]3[CH:44]=[C:45]([C:47]([OH:49])=O)[N:46]=[C:41]3[CH2:40][CH2:39]2)=[CH:34][C:33]=1[CH3:50].[F:51][C:52]([F:66])([F:65])[C:53]1[CH:54]=[C:55]([N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH:56]=[CH:57][CH:58]=1>CN(C=O)C>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][N:42]3[CH:44]=[C:45]([C:47]([N:62]4[CH2:61][CH2:60][N:59]([C:55]5[CH:56]=[CH:57][CH:58]=[C:53]([C:52]([F:65])([F:66])[F:51])[CH:54]=5)[CH2:64][CH2:63]4)=[O:49])[N:46]=[C:41]3[CH2:40][CH2:39]2)=[CH:34][C:33]=1[CH3:50]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Cc1cc(C2CCc3nc(C(=O)O)cn3C2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C2CCc3nc(C(=O)N4CCN(c5cccc(C(F)(F)F)c5)CC4)cn3C2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (295 mg; 0.92 mmol) and N-methylmorpholine (253 μl; 232 mg; 2.3 mmol) were added to a solution of 6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (210 mg; 0.68 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-(3-trifluoromethylphenyl)piperazine (173 μl; 212 mg; 0.92 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and poured onto water. The precipitated solid was purified by column chromatography on silica gel (chloroform). Yield: 166 mg (50%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.C(OO)(=[O:17])C.C(O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]1[CH:7]=[N+:8]([O-:17])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)OO
Reactant: Clc1cccc(Oc2cccnc2)c1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: [O-][n+]1cccc(Oc2cccc(Cl)c2)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A solution of 110 g of 3-(m-chlorophenoxy)pyridine [Agr. Biol. Chem., 34, 68 (1970)] at 35° C. in 125 ml of glacial acetic acid is treated with 112 g of 40% peracetic acid in acetic acid in four equal portions. The mixture is held at 27° C. for 16 hours and heated at reflux for 1 hour. The mixture is cooled to 70° C., 100 ml of isopropanol is added and the mixture is heated at 95° C. for 1 hour. The warm mixture is concentrated at reduced pressure, dissolved in 500 ml of dichloromethane and extracted with excess 25% sodium hydroxide solution. The dichloromethane is removed at reduced pressure and the 3-(m-chlorophenoxy)pyridine N-oxide is isolated by distillation; 150°-152° C. at 0.15 mm, mp 72°-75° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[OH:22]>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[O:22][C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: c1ccc(CN2CC3OC3C2)cc1
Solvent: ClCCl
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1c(Cl)cccc1Cl

Procedure:
A mixture of 35.0 g. of 1-benzyl-3,4-epoxypyrrolidine and 32.6 g. of 2,6-dichlorophenol was heated at 125° C. for 3 hr. The mixture was cooled, dissolved in methylene chloride and extracted with dilute sodium hydroxide. The residue after the solvent was evaporated was purified by column chromatography. The product was eluted with 30% ethyl acetate in benzene and crystallized from cyclohexane. Yield was 43 g (64%), m.p. 78°-80° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1>CCCCCC.[Pd]>[C:9]([O:11][CH2:12][CH3:13])(=[O:10])/[CH:8]=[CH:7]\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C#Cc1ccccc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)/C=C\c1ccccc1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
Ethyl phenylpropiolate (10.8 g, 0.062 mol) was dissolved in hexane (540 ml), followed by addition of quinoline (11.2 g) and palladium on calcium carbonate (Lindlar catalyst, 3.6 g). The resulting reaction mixture was stirred under hydrogen (1 atm) at room temperature, and the progress of the reaction was monitored closely by GC analysis. The reaction was stopped by displacement of the hydrogen atmosphere with nitrogen once the rate of absorption of hydrogen was observed to decrease abruptly. The resulting mixture was faltered through a pad of diatomaceous earth and the filtrate was dried over Na2SO4. Solvent was removed under reduced pressure. Then the residue was distilled under vacuum (2.5 mm Hg, at 98°-100° C.) to provide 10.08 g of cis-ethyl cinnamate, for a yield of nearly 95%. By GC analysis, this product mixture was found to contain 5.7% over-reduced alkane and 3.5% trans-ethyl cinnamate, but was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:26][OH:27])=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:26][O:27][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:9]([CH2:11][N:12]3[CH2:13][CH2:14][N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[CH2:16][CH2:17]3)[N:10]=2)[CH:7]=1
Reactant: OCc1c(CN2CCN(c3ccc(Cl)cc3Cl)CC2)nc2ccc(Cl)cn12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(N2CCN(Cc3nc4ccc(Cl)cn4c3COCc3ccccc3)CC2)c(Cl)c1
Reaction time: 0.12 h

Procedure:
To 6-chloro-2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]imidazo[1,2-a]pyridine-3-methanol (Example 44; 0.0651 g) in THF (1 mL) is added sodium hydride (Aldrich, 60% dispersion in mineral oil; 0.0067 g). After 7 min, benzyl bromide (Aldrich; 0.020 mL) is added and the mixture is stirred for an additional 4.5 h. at which time it is partitioned between dichloromethane and aq. sodium bicarbonate/brine. The organic layers are filtered through sodium sulfate and concentrated, and the residue is chromatographed on silica gel using methanol/dichloromethane (2/98) to give 0.061 g of 6-chloro-2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]-3-[(phenylmethoxy)methyl]imidazo[1,2-a]pyridine. The methanesulfonic acid salt is prepared by dissolving the product in dichloromethane and adding methanesulfonic acid (1 equivalent) and concentrating the mixture under reduced pressure. Crystallization from ethyl acetate/hexane affords 0.050 g of the title compound; mp 159-160.5° C.; MS m/z 514, 516; IR (mineral oil) 806, 1170, 1042, 1188, 1480 cm-1. 1H NMR (CDCl3) δ2.68, 3.02, 3.75, 4.57, 4.91, 6.92, 7.17, 7.36, 7.53, 8.14.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][C:12]3[N:13]([CH3:18])[C:14]([NH:16][CH3:17])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[CH3:21][N:8]([C:9]1[CH:20]=[CH:19][C:12]2[N:13]([CH3:18])[C:14]([NH:16][CH3:17])=[N:15][C:11]=2[CH:10]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:24]=[C:25]([S:29]([NH2:32])(=[O:30])=[O:31])[CH:26]=[CH:27][CH:28]=2)[N:7]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CNc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Product: CNc1nc2cc(N(C)c3ccnc(Nc4cccc(S(N)(=O)=O)c4)n3)ccc2n1C

Procedure:
The title compound was prepared following the procedure of Example 1 with N5-(2-chloropyrimidin-4-yl)-N2,N5,1-trimethyl-1H-benzimidazole-2,5-diamine (60 mg, 0.20 mmol) and 3-amino-benzenesulfonamide (34 mg, 0.20 mmol) as a white solid (40 mg, 42%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.51 (s, 1H), 8.61 (s, 1H), 7.77-7.82 (M, 2H), 7.26-7.39 (m, 6H), 7.17 (s, 1H), 6.92 (d, J=7.8 Hz, 1H), 5.66 (d, J=6.0 Hz, 1H), 3.55 (s, 3H), 3.47 (s, 3H), 2.95 (d, J=4.2 Hz, 3H). MS (ESI) m/z=439 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:14][CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)([OH:21])[C:17]([F:20])([F:19])[F:18])[CH3:13]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:14]([CH2:12][CH3:13])[CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)([OH:21])[C:17]([F:18])([F:20])[F:19])=[O:5]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(Cl)c1c(F)cccc1Cl
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(F)cccc1Cl

Procedure:
Prepared similarly to Example 48 from 2-chloro-6-fluorobenzoylchloride and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11]>>[CH3:13][O:12][C:10](=[O:11])[C:9](=[O:14])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Nc1ccncc1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ccncc1

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 4-aminopyridine and methyl chlorooxoacetate.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.O.[CH2:18]([OH:20])[CH3:19]>>[CH2:18]([O:20][CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:19]
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: CCO
Solvent: O
Product: CCOCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 9-chloromethylanthracene (5.2 g, 23 mmole) obtained in Synthesis Example 2-(1) in ethanol (700 ml) was reacted with stirring for 10 hours at room temperature, poured into H2O (700 ml), and extracted with methylene chloride (500 ml×1). The resulting organic layer was dried over anhydrous MgSO4 and evaporated. The residual crude solid (4.25 g) was recrystallized from 50% THF/H2O to give 4.02 g of 9-ethoxymethylanthracene as orange yellow crystals, mp. 74-75° C.