Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[C:17]([O:19][CH3:20])=[O:18])[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].O[CH:22]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:29][C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>C(O)C.C(O)(=O)C>[CH:24]1[C:23]2[CH:22]([CH:8]([C:6](=[O:7])[C:5]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)CC(=O)c1ccc(C(=O)OC)c(OC)c1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C(=O)c1ccc(C(=O)OC)c(OC)c1)C1c2ccccc2Oc2ccccc21
Temperature: 25 °C

Procedure:
To a stirred solution of ethyl 3-methoxy-4-methoxycarbonylbenzoylacetate (4.1 g, 14.6 mmol) in a mixture of ethanol (30 ml) and acetic acid (30 ml) was added portionwise 9-hydroxyxanthene (3.2 g, 16.1 mmol). After stirring for 2 weeks at room temperature, the solution was concentrated in vacuo, diluted with water and extracted with dichloromethane (2×). The combined extracts were washed with a saturated solution of sodium bicarbonate, water and dried over magnesium sulphate. Filtration and evaporation gave ethyl 2-(9H-xanthen-9-yl)-2-(3-methoxy-4-methoxycarbonyl-benzoyl)acetate as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=[C:21]([C:23]([OH:25])=O)[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:49]=[CH:48][C:40]([CH2:41][N:42]2[CH:46]=[C:45]([NH2:47])[CH:44]=[N:43]2)=[CH:39][CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:34])[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[CH:20]=[C:21]([C:23](=[O:25])[NH:47][C:45]2[CH:44]=[N:43][N:42]([CH2:41][C:40]3[CH:48]=[CH:49][C:37]([O:36][CH3:35])=[CH:38][CH:39]=3)[CH:46]=2)[CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(Cn2cc(N)cn2)cc1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)O)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Product: COc1ccc(Cn2cc(NC(=O)c3cc(-c4cc5ccccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1

Procedure:
The title compound was prepared according to the experimental used in Example 1, Step 4 using intermediate (1c) and 1-(4-methoxy-benzyl)-1H-pyrazol-4-ylamine. After the usual aqueous work up, the resultant crude product was purified by flash chromatography on SiO2 eluting with hexane—50% ethyl acetate/hexane. This afforded the title compound as a pink solid, 180 mg, 50%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]([S:16][CH3:17])=[N:12][N:11]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[Cl:18][CH2:19][C:20]([N:9]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:8])[C:10]1[N:14]([CH3:15])[C:13]([S:16][CH3:17])=[N:12][N:11]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: CSc1nnc(Nc2c(C)cccc2C)n1C
Solvent: Cc1ccccc1
Product: CSc1nnc(N(C(=O)CCl)c2c(C)cccc2C)n1C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a stirred solution of 6.1 g (0.0232 mol) 3-(2,6-dimethylphenylamino)-4-methyl-5-methylthio-1,2,4-triazole in 150 ml toluene was added quickly 2.7 g (0.024 mol) chloroacetyl chloride. An exotherm ensued and the temperature rose to 100° C., followed by separation of an oil which solidified. The reaction mixture was stirred at 100°-105° C. for 1 hour, cooled and diluted with 50 ml saturated sodium bicarbonate and 20 ml dichloromethane. The clear organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give a clear oil. The oil was crystallized from ethyl ether to give 7.4 g of product, as a pale yellow solid, m.p. 145°-147° C. The product is tabulated in Table I as Compound No. 14-B.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]([C@H:27]([CH3:73])[C@H:28]([CH2:54][N:55]1[CH:63]=[N:62][C:61]2[C:56]1=[N:57][CH:58]=[N:59][C:60]=2[NH:64][C:65](=[O:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[CH2:29][O:30][C:31]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[Si](C(C)(C)C)(C)C>C1COCC1>[C:65]([NH:64][C:60]1[N:59]=[CH:58][N:57]=[C:56]2[C:61]=1[N:62]=[CH:63][N:55]2[CH2:54][C@@H:28]([C@H:27]([OH:19])[CH3:73])[CH2:29][O:30][C:31]([C:46]1[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=1)([C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: COc1ccc(C(OC[C@@H](Cn2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](C)O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@@H](Cn2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 48 h
Yield: 96.4 %

Procedure:
A solution of tetrabutylammonium fluoride 1M in THF (3 ml) was added to a solution of 13 (1.1 g, 1.45 mmol) in 10 ml of THF. The reaction was kept at room temperature for 2 days until no staring material was seen by HPLC analysis. The reaction was concentrated and partitioned between water and ethyl acetate. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated. The resulting material was chromatographed on silica eluting with a gradient of acetone (0-40%) in ethyl acetate. Concentration of the pure product fractions afforded 0.9 g (96%) of 14 as a white amorphous solid. 1H NMR (DMSO-d6): δ 11.12 (s, 1H), 8.70 (s, 1H), 8.34 (s, 1H), 8.05 (d, J=8.7 Hz, 2H), 7.65 (m, 1H), 7.56 (t, J=7.5 Hz, 2H), 7.18 (m, 5H), 7.04 (m, 4H), 6.77 (m, 4H), 4.79 (d, J=4.8 Hz, 1H), 4.39 (m, 2H), 3.80 (m, 1H), 3.71 (s, 6H), 3.09 (m, 1H), 2.88 (m, 1H), 2.31 (m, 1H), 1.03 (d, J=6.3 Hz, 3H).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][C:8]1=[O:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:31]([C:33]1[CH:46]=[CH:45][C:36]([CH2:37][N:38]2[C:42]([CH:43]=O)=[CH:41][N:40]=[CH:39]2)=[CH:35][C:34]=1[F:47])#[N:32].CCOC(C)=O>ClCCCl>[C:31]([C:33]1[CH:46]=[CH:45][C:36]([CH2:37][N:38]2[C:42]([CH2:43][N:10]3[CH2:11][CH2:12][N:7]([CH2:6][C:5]4[CH:14]=[CH:15][CH:16]=[C:3]([OH:2])[CH:4]=4)[C:8](=[O:13])[CH2:9]3)=[CH:41][N:40]=[CH:39]2)=[CH:35][C:34]=1[F:47])#[N:32]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: O=C1CNCCN1Cc1cccc(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CN2CCN(Cc3cccc(O)c3)C(=O)C2)cc1F
Reaction time: 16 h

Procedure:
To a solution of the amine hydrochloride from Step K (theoretically 0.22 mmol) in 2 mL of 1,2-dichloroethane was added 4 Å powdered molecular sieves (100 mg), followed by sodium triacetoxyborohydride (70 mg, 0.33 mmol). The aldehyde from Step G (51 mg, 0.22 mmol) was added, and the reaction was stirred for 16 hours. The reaction was poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a pale yellow foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].O>CN(C=O)C>[CH3:34][O:33][C:31](=[O:32])[CH2:30][NH:22][C:10]1[CH:11]=[CH:12][C:13]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1OCc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNc1ccc(Oc2ccccc2)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-benzyloxy-4-phenoxyphenylamine (400 mg, 1.37 mmol) and K2CO3 (284 mg, 2.05 mmol) in DMF (5 mL) is added methyl bromoacetate (231 mg, 1.51 mmol). The mixture is stirred at 60° C. for 90 min., then an additional methyl bromoacetate (50 mg) is added and the mixture is stirred at 60° C. for 1 h. The mixture is allowed to cool to ambient temperature, then poured into water and extracted into EtOAc. The organic phase is washed with water (3×), saturated NaCl (1×) and dried over Na2SO4. The solvent is removed under reduced pressure to afford (2-benzyloxy-4-phenoxyphenylamino)acetic acid methyl ester. This is used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:12]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][Br:12])=[CH:6][N:7]=1
Reactant: BrP(Br)Br
Reactant: OCCc1ccc(Br)nc1
Solvent: ClCCl
Product: BrCCc1ccc(Br)nc1
Yield: 87.8 %

Procedure:
Alcohol 289 (1.75 g, 8.66 mmol) was treated with phosphorous tribromide (5.0 mL, 53 mmol) and the mixture was heated for 5 min, until the solid had melted and re-solidified. The mixture was cooled, treated with ice and partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was collected, washed with saturated aqueous sodium bicarbonate and brine, dried (anhydrous MgSO4), filtered and concentrated. Silica gel chromatography of the residue (eluent DCM) provided title compound 290 (2.0 g, 7.6 mmol, 87% yield) as a colorless solid. MS (M+H): 266.0
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][CH:7]=[CH:6][N:5]2[CH:18]=1.[N:19](OCCCC)=[O:20]>O1CCOCC1>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8][CH:7]=[CH:6][N:5]2[C:18]=1[N:19]=[O:20]
Reactant: Cc1cn2ccnc(OCc3ccccc3)c2n1
Reactant: CCCCON=O
Solvent: C1COCCO1
Product: Cc1nc2c(OCc3ccccc3)nccn2c1N=O

Procedure:
A solution of 14.2 g 2-methyl-8-phenylmethoxyimidazo[1,2-a]pyrazine, 129.3 g n-butyl nitrite and 142 ml p-dioxane was heated under reflux for 0.5 hr. and decanted from a small amount of gum. The supernatant solution was stirred under vacuum (40°/0.1 mm) and the residue azeotroped with cyclohexane to give 2-methyl-3-nitroso-8-phenylmethoxyimidazo[1,2-a]pyrazine as a soft, green solid which was identified by pmr and ms and immediately reduced (as in Example 6) without further purification.
Reaction SMILES: C([CH:3]([C:9]([CH3:20])([CH3:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[C:4]([O:6]CC)=[O:5])#N.[OH-].[K+].O>C=C>[CH3:19][C:9]([CH3:20])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C#N)C(C)(C)Cc1cccc(OC)c1
Agent: C=C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(CC(C)(C)CC(=O)O)c1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A solution of ethyl 2-cyano-3,3-dimethyl-4-(3-methoxyphenyl)butanoate (9.0 g, 0.033 mol) and KOH (9.2 g, 0.163 mol) in ethylene gylcol (100 mL) was heated at 180° C. for 2 days. The solution was cooled to room temperature, poured into water (200 mL) and extracted with ether (100 mL). The organic layer was separated, dried (MgSO4) and evaporated to afford the acid (6.7 g, 0.03 mol)as brown oil, which was used without further purification. 1H NMR (360 MHz, CDCl3) δ 1.06 (6H, s), 2.24 (2H, s), 2.66 (2H, s), 3.81 (3H, s), 6.74-6.79 (3H, m), 7.19 (1H, t, J=8.1 Hz). MS (ES+) 223 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C@@H:5]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][C:12]([F:22])=[CH:13][C:14]=3[S:18]([CH3:21])(=[O:20])=[O:19])[C:9]=2[C:8](=[O:23])[CH2:7][CH2:6]1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([C@H:33](O)[CH3:34])=[CH:29][CH:28]=1>>[F:22][C:12]1[CH:11]=[C:10]2[C:15](=[C:14]([S:18]([CH3:21])(=[O:19])=[O:20])[CH:13]=1)[N:16]([C@H:33]([C:30]1[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:32][CH:31]=1)[CH3:34])[C:17]1[C@@H:5]([CH2:4][C:3]([OH:2])=[O:24])[CH2:6][CH2:7][C:8](=[O:23])[C:9]2=1
Reactant: C[C@@H](O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C[C@H]1CCC(=O)c2c1[nH]c1c(S(C)(=O)=O)cc(F)cc21
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)n1c2c(c3cc(F)cc(S(C)(=O)=O)c31)C(=O)CC[C@@H]2CC(=O)O

Procedure:
The procedures described in Example 1 were followed using compound of Step 1 and (1R)-1-[4-(trifluoromethyl)phenyl]ethanol to provide the title compound following the hydrolysis of the corresponding methyl ester. MS (+APCI) m/z 511.9 (M)+
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:2]=1[O:21][C:18]1[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=1
Reactant: Clc1ncccc1-c1ccncc1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2-c2ccncc2)cc1
Temperature: 25 °C

Procedure:
To a 50 mL round-bottomed flask was added 2-chloro-3-(pyridin-4-yl)pyridine (0.75031 g, 3.9 mmol), 4-aminophenol (0.4302 g, 3.9 mmol), cesium carbonate (0.38 ml, 4.7 mmol) in DMSO at 80° C. Upon completion, the reaction was allowed to cool to room temperature. The reaction mixture was diluted with water (10 ml) and extracted with DCM (3 15 mL). The organic extract was washed with water (1 10 mL), brine (1 10 mL), dried with magnesium sulfate, filtered and concentrated. The residue was taken up in DCM and was loaded onto a SCX cartridge. The impurities were filtered off with DCM and MeOH. 4-(3,4′-Bipyridin-2-yloxy)aniline was filtered from cartridge using 2.0M ammonia in MeOH (MS 264.0).
Reaction SMILES: [Cl:1][CH:2]([CH2:13]Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:4].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.O>[Cl:1][C:2](=[CH2:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Nc1ccc(Cl)cc1)C(Cl)CCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(Cl)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 51.1 %

Procedure:
To a stirred solution of 17.0 grams (0.067 mole) of 2,3-dichloro-N-(4-chlorophenyl)propanamide (Step A product) in 300 ml of toluene was added dropwise 11.3 grams (0.074 mole) of 1,8-diazabicyclo[5.4.0]-undec-7-ene in 100 ml of toluene. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 60 hours. The reaction mixture was diluted with distilled water and transferred to a separatory funnel. The organic layer was separated and washed twice with water and twice with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual solid. The solid was recrystallized from methylcyclohexane using silica gel as a decolorant to give 7.4 grams of 2-chloro-N-(4-chlorophenyl)-2-propenamide; mp 105°-106.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21]CC=C)=[CH:17][CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=CCOc1ccc(C(=O)C=Cc2ccc(OC)c(OC)c2)cc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(C=CC(=O)c2ccc(O)cc2)cc1OC
Temperature: 80 °C
Yield: 29.3 %

Procedure:
486 mg (1.5 mmol) of 3,4-dimethoxy-4′-allyloxychalcone was dissolved in a mixture of 7.5 ml of methanol and 1.5 ml of water. To the solution were added 150 mg of p-tolu-enesulfonic acid and 150 mg of palladium on carbon (10%) and the solution was heated to 80° C. for 2 h in a sealed flask. The reaction mixture was filtered and poured into a mixture of 10 ml of an aqueous 10% solution of sodium bicarbonate and 10 ml of a saturated aqueous solution of sodium chloride. The mixture was extracted with 15 ml of ethyl acetate and concentrated in vacuo. The residue was recrystallized from methanol to give 0.125 g (25%) of 3,4-dimethoxy-4′-hydroxychalcone (m.p. 193-198° C.) identical to that described by A.v.n Wacek, and E. David, Ber. 70 (1937), 190 (m.p. 208° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH3:14][NH2:15]>C1COCC1>[CH3:14][N:15]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1
Reactant: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Reactant: CN
Solvent: C1CCOC1
Product: CN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with THF (350 mL), 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 101j (10.0 g, 32.2 mmol), 2M methylamine solution in THF (113 mL, 225 mmol) and stirred at room temperature for 72 h. After this time the reaction was concentrated to dryness under reduced pressure, and the resulting solid was stirred with a mixture of ethyl acetate (75 mL) and 10% aqueous potassium carbonate (75 mL). The aqueous layer was separated and extracted with ethyl acetate (2×75 mL). The combined organic extracts were washed with 10% aqueous potassium carbonate (75 mL), followed by brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate concentrated under reduced pressure to afford 5-methyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 101k in a 97% yield (5.70 g) as a yellow solid: 1H NMR (300 MHz, CDCl3) d 6.62 (s, 1H), 4.28 (t, 2H, J=5.4 Hz), 3.67 (s, 2H), 2.95 (t, 2H, J=5.4 Hz), 2.52 (s, 3H); MS (ESI+) m/z 183.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[CH:11](OCC)(OCC)OCC>C(O)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][CH:11]=[N:10][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cc(F)c(F)cc1N
Solvent: O=CO
Product: Fc1cc2nc[nH]c2cc1F
Temperature: 100 °C

Procedure:
A stirred mixture of 4,5-difluorobenzene-1,2-diamine (1.40 g, 9.7 mmol) from the previous step, formic acid (2.0 mL), and triethyl orthoformate (20 mL) was heated at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5% MeOH in DCM to afford 5,6-difluoro-1H-benzo[d]imidazole as (1.12 g, 75%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.44 (m, 2H); LCMS (ESI) m/z 155 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+]>ClCCl>[C:30]([N:13]1[CH2:14][CH2:15][CH2:16][N:10]([CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:12]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCCN(CCC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The resulting 1-(3,3-diphenylpropyl )homopiperazine was dissolved in 3 mL of dichloromethane, followed by adding 107 mg of triethylamine and 140 mg of benzoyl chloride. After the mixture was stirred at room temperature for 6 hours, it was mixed with 20 mL of aqueous 2N sodium hydroxide and extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, hexane/ethyl acetate 4:6) to obtain 249 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure and the residue was dried to give the hydrochloride salt of the titled compound.
Reaction SMILES: CN(OC)[C:3](=[O:16])[CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([CH:6]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH2:5][CH2:4][C:3]([CH2:4][CH2:5][CH:6]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CON(C)C(=O)CCCc1c[nH]c2ccccc12
Solvent: C1CCOC1
Product: O=C(CCC(Cc1ccccc1)c1c[nH]c2ccccc12)CCC(Cc1ccccc1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
To a solution of 147 mg (0.60 mmol) of amide 139 in 4.0 mL of THF at -78° C. was added 1.31 mL (1.31 mmol) of benzylmagnesium chloride (1.0M in Et2O) and the reaction mixture was allowed to warm to room temperature and stir for 3 h. The reaction was quenched with 5% KHSO4 and extracted into ether. The combined ethereal layers were washed with brine and dried over MgSO4. Flash chromatography (elution with 25% ether in hexane) gave 108 mg of the ketone 140. 1H NMR consistent with structure.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11]C(CCC)CCC)[CH:5]=[C:4]([CH3:19])[N:3]=1.[Br:20][C:21]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:22]=1[NH2:23]>C(Cl)Cl>[Br:20][C:21]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:22]=1[N:23]([CH:21]([CH2:27][CH2:26][CH3:28])[CH2:22][CH2:24][CH3:25])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([CH3:19])[N:3]=1
Reactant: CCCC(CCC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Reactant: CC(C)c1ccc(N)c(Br)c1
Solvent: ClCCl
Product: CCCC(CCC)N(c1ccc(C(C)C)cc1Br)c1nc(C)cc(N)c1[N+](=O)[O-]
Yield: 86.3 %

Procedure:
2-Chloro-6-methyl-3-nitro-N-(1-propylbuty)pyridin-4-amine (0.5 g, 1.75 mmol) and 2-bromo-4-isopropylaniline (0.74 g, 3.5 mmol) were heated at 140° C. for 4.5 h. After cooling it was dissolved in CH2Cl2 and filtered through a short column of silica gel. The filtrate was concentrated and chromatographed on silica gel (5% EtOAc/hexanes eluting solvent) to give the product (0.7 g).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:31]C(=O)C)[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:17]=1.[ClH:35]>CO>[ClH:35].[NH2:31][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:17]=2)=[C:9]([F:8])[CH:10]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1
Yield: 76 %

Procedure:
A mixture of N-(3-fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy)phenyl)acetamide trifluoroacetate (40 mg), MeOH (1 mL), and 6 M HCl (0.2 mL) was heated at reflux for 3 h. The reaction mixture was concentrated on a rotary evaporator and the residue lyophilized to give the title compound (30 mg, 76%) as a white solid. 1H NMR (DMSO-d6) δ 11.12 (br s, 1H), 8.85 (br s, 1H), 7.95 (d, 1H, J=7.2 Hz), 7.08 (dd, 1H, J=8.8, 8.8 Hz), 6.65-6.63 (m, 2H), 6.54 (d, 1H, J=8.3 Hz), 6.31 (br s, 1H), 3.85 (m, 6H), 3.33 (m, 6H); MS(ESI−) m/z 373.14 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH3:17]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([NH:8][C:9]([NH2:17])=[S:10])[CH:7]=1
Reactant: Fc1ccc(N2CCOCC2)c(N=C=S)c1
Reactant: N
Product: NC(=S)Nc1cc(F)ccc1N1CCOCC1

Procedure:
Reaction of 5-fluoro-2-morpholinophenyl isothiocyanate (5.8 g) with 33% ethanolic ammonia solution (30 ml) at room temperature for 3 hours gave 1-(5-fluoro-2-morpholinophenyl)thiourea as a white solid (m.p. 195-196).