Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:16][CH2:17][OH:18])[CH2:9][CH2:10][CH2:11][C:12](OC)=O)=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:23][NH:24][C:25]([NH2:27])=[NH:26].N1C=CC=CC=1>C(Cl)(Cl)Cl.CO.C(O)(=O)C>[NH2:27][C:25]1[NH:24][N:23]=[C:12]([CH2:11][CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:16][CH2:17][OH:18])[N:26]=1
Reactant: COC(=O)CCCN(CCO)c1ccc(F)cc1
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: Nc1nc(CCCN(CCO)c2ccc(F)cc2)n[nH]1
Temperature: 125 °C
Yield: 45.7 %

Procedure:
A mixture of methyl 4-[(4-fluorophenyl)(2-hydroxyethyl)amino]butanoate (1.1 g, 4.31 mmol), aminoguanidine bicarbonate (1.47 g, 10.78 mmol), and pyridine (12 mL) was added to a 200 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser and heated to 125° C. using an oil bath. Progress of the reaction was monitored by TLC using chloroform:methanol: acetic acid (9:1:0.2) (Rf starting material=0.8, Rf product=0.1). During the course of heating, additional portions of aminoguanidine bicarbonate were added at 15 h and 22 h (2×1.0 g, 14.7 mmol total). After 37 hours of heating, the reaction was complete by TLC analysis and was allowed to cool to ambient temperature. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate (60 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by silica gel column chromatography using 100% ethyl acetate, followed by 10% methanol in dichloromethane to afford the title compound as an oil (0.55 g, 45% yield).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:26]=[CH:25][C:14]([O:15][CH2:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)CBr
Reactant: N#Cc1ccc(COc2ccc([C@@H]3C[C@H]3N)cc2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN[C@@H]1C[C@H]1c1ccc(OCc2ccc(C#N)cc2)cc1
Reaction time: 22 h
Yield: 43.5 %

Procedure:
A solution of methyl bromoacetate (0.08 mL, 0.91 mmol) in CH3CN (6 mL) was added, over a period of 15 min, to a solution of 4-({4-[(trans)-2-aminocyclopropyl]phenoxy}methyl)benzonitrile (0.22 g, 0.82 mmol) and DIPEA (0.28 mL, 1.64 mmol) in CH3CN (8 mL) at −10° C. The reaction was allowed to reach room temperature and stirred for 22 h. After removal of the solvent, the crude residue was purified by column chromatography on silica gel (2-5% MeOH/CH2Cl2) affording 0.12 g of methyl[((trans)-2-{4-[(4-cyanobenzyl)oxy]phenyl}cyclopropyl)amino]acetate [Rf=0.5 (5% MeOH/CH2Cl2), pale yellow oil, 44% yield].
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])[NH:3]1>CO.[Pd]>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[NH:3]1
Reactant: CCOC(=O)/C=C/c1cccc2c1CCC(=O)N2
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCc1cccc2c1CCC(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 10% Pd/C (5 mg) and ethyl (2E)-3-(2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)acrylate from Step B (16 mg, 0.065 mmol) was stirred vigorously in MeOH (2 mL) under an atmosphere of hydrogen (ca. 1 atm). After 4 h, the mixture was filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated. The residue was dissolved in MeOH (1 mL) and 1 N aqueous NaOH (0.1 mL) and the resulting mixture was stirred at ambient temperature for 18 h. To the reaction mixture was added 1 N aqueous HCl (0.1 mL) and the resulting mixture was concentrated to dryness under reduced pressure to give the title compound. MS: m/z=220 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: OB(O)c1ccccc1F
Product: Fc1ccccc1-c1ccc2cc[nH]c2c1

Procedure:
Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 2-fluorophenylboronic acid: ESMS m/e: 211.9 (M+H)+.
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.CO>>[CH:11]#[C:10][C:9]1[CH:12]=[CH:13][C:6]([OH:5])=[CH:7][CH:8]=1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Solvent: CO
Product: C#Cc1ccc(O)cc1
Reaction time: 0.08 h

Procedure:
A 1-liter flask was charged with 500 ml of tetrahydrofuran as a solvent and 0.01 mol of sec-butyl lithium as an initiator. To the solution at −78° C. was added 30 g of p-tert-butoxystyrene. With stirring, polymerization reaction was effected for 30 minutes. The reaction solution turned red. For producing a branched polymer, 0.005 mol of p-chloromethylstyrene was added to the reaction solution whereupon reaction was effected for 5 minutes. The reaction solution was red. Further 15 g of p-tert-butoxystyrene was added. With stirring, polymerization reaction was effected for 30 minutes. Polymerization was stopped by adding 0.1 mol of methanol to the reaction solution.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[S:13])[NH2:12])=[CH:7][CH:6]=1)[CH3:2].Br[CH2:16][C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=O.Br>C(O)(C)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:13][CH:16]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=C(CBr)c1cccnc1
Reactant: CCOC(=O)c1ccc(C(N)=S)cc1
Agent: Br
Solvent: CCOCC
Solvent: CC(C)O
Product: CCOC(=O)c1ccc(-c2nc(-c3cccnc3)cs2)cc1

Procedure:
4-Thiocarbamoyl-benzoic acid ethyl ester (CAS 78950-31-9) (0.4 g, 1.91 mmol), and 2-Bromo-1-pyridin-3-yl-ethanone; hydrobromide (CAS 17694-68-7) (0.537 g, 1.91 mmol) is placed in a 100 mL flask and dissolved in 20 mL of isopropyl alcohol. The mixture is heated to reflux for 1.5 hours and cooled and diluted with 40 mL of diethyl ether. The resulting solid is filtered and dissolved in a mixture of dichloromethane and saturated sodium bicarbonate solution. The organics are separated, dried over sodium sulfate, filtered and concentrated to provide 0.565 g of the titled compound. MS (m/e) 311.1 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]2[CH:11]([O:21]2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCC1CC=CCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCC2OC2C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 166.1 %

Procedure:
To a solution of cyclohex-3-enylmethyl-carbamic acid tert-butyl ester (1.5 g, 7.10 mmol) in 20 ml of anhydrous dichloromethane was added 3-chloroperoxybenzoic acid (2.45 g, 14.2 mmol) under cooling. The resulting mixture was stirred for 19 hours at room temperature and washed with saturated sodium bicarbonate and 0.5M aqueous solution of sodium thiosulphate. The aqueous phase was extracted three times with dichloromethane and the combined organic phases were washed with brine. The resulting organic phase was dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield 1.48 g of crude product. Column chromatography of 3.17 g of crude product (silica, petrol ether/ethyl acetate=3/1) resulted in (7-oxa-bicyclo[4.1.0]hept-3-ylmethyl)-carbamic acid tert-butyl ester (Rf=0.19, 2.68 g, 81% yield) as colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH2:44][C@H:45]1[CH2:53][O:52][CH2:51][C@H:50]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[C@@H:49]([O:62][CH2:63][CH:64]([CH3:66])[CH3:65])[C@H:48]([CH3:67])[O:47][C:46]1=[O:68]>C(Cl)Cl>[OH:1][C:2]1[C:3]([C:10]([NH:44][C@H:45]2[CH2:53][O:52][CH2:51][C@H:50]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=3)[C@@H:49]([O:62][CH2:63][CH:64]([CH3:65])[CH3:66])[C@H:48]([CH3:67])[O:47][C:46]2=[O:68])=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: Cc1ccc(C[C@H]2COC[C@H](N)C(=O)O[C@@H](C)[C@@H]2OCC(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3ccc(C)cc3)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Temperature: 25 °C
Reaction time: 7 h
Yield: 76.8 %

Procedure:
To a mixture of 3-hydroxy-4-methoxypicolinic acid (0.198 g, 1.17 mmol), HATU (0.47 g, 1.25 mmol), and N-methylmorpholine (0.47 g, 4.7 mmol) in CH2Cl2 (9 mL) was added (3S,7S,8R,9S)-3-amino-8-isobutoxy-9-methyl-7-(4-methylbenzyl)-1,5-dioxonan-2-one (272 mg, 0.78 mmol), and the tan mixture was stirred at room temperature for 7 h. The resulting homogeneous solution was adsorbed to Celite® and purified by flash chromatography (SiO2, 0→30% acetone/hexanes) to give 3-hydroxy-N-((3S,7S,8R,9S)-8-isobutoxy-9-methyl-7-(4-methylbenzyl)-2-oxo-1,5-dioxonan-3-yl)-4-methoxypicolinamide (0.30 g, 77%) as a white foam: 1H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 8.54 (d, J=8.3 Hz, 1H), 7.97 (d, J=5.2 Hz, 1H), 7.09 (d, J=2.1 Hz, 4H), 6.85 (d, J=5.2 Hz, 1H), 5.01 (m, 2H), 4.02 (dd, J=11.7, 7.3 Hz, 1H), 3.92 (s, 3H), 3.46 (m, 4H), 3.34 (dd, J=8.3, 6.5 Hz, 1H), 3.13 (m, 2H), 2.31 (s, 4H), 1.93 (m, 2H), 1.50 (d, J=6.4 Hz, 3H), 0.96 (d, J=6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.15, 168.90, 155.31, 148.71, 140.62, 136.76, 135.58, 130.20, 129.15, 129.05, 109.56, 84.61, 79.28, 75.92, 72.53, 72.16, 56.08, 51.53, 47.47, 34.60, 29.20, 21.03, 19.50, 18.83; HRMS-ESI (m/z) [M+H]+ calcd for C27H36N2O7, 500.2523. found, 500.2529.
Reaction SMILES: OC1C(C(OCC)=O)=CN=C(N2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)N=1.[OH:22][C:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=[C:25]([N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36][C@H:35]2[CH3:43])[N:24]=1>>[CH3:43][C@@H:35]1[CH2:36][C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:34]1[C:25]1[N:24]=[C:23]([O:22][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=1
Reactant: CCOC(=O)c1cnc(N2c3ccccc3C[C@H]2C)nc1O
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1O
Product: CCOC(=O)c1cnc(N2c3ccccc3C[C@H]2C)nc1OC(C)c1ccccc1

Procedure:
In the same manner as in Reference Example 3-1 using ethyl 4-hydroxy-2-(2,3-dihydro-1H-indol-1-yl)-5-pyrimidinecarboxylate and ethyl 4-hydroxy-2-[(R)-2-methyl-2,3-dihydro-1H-indol-1-yl]-5-pyrimidinecarboxylate as starting materials, compounds of Reference Examples 26 and 27 were synthesized.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[N:12]([Si](C(C)C)(C(C)C)C(C)C)[CH:11]=2)O)=[CH:6][CH:5]=[C:4]([NH:30][C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>ClCCCl>[F:1][C:2]1[N:3]=[C:4]([NH:30][C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1
Reactant: COc1ccc(Nc2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: O
Product: COc1ccc(Nc2ccc(Cc3c[nH]c4ncc(C)cc34)c(F)n2)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To [2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (68, 0.220 g, 0.411 mmol) in 20.0 mL of 1,2-dichloroethane, triethylsilane (2.0 mL, 12 mmol) and trifluoroacetic acid (1.0 mL, 13 mmol) are added and the reaction stirred at 80° C. for 3 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-3019, 105.1 mg). MS (ESI) [M+H+]+=364.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1F>CN(C=O)C>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: Fc1ccccc1F
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccccc2F)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
Dissolve 1-methyl-piperidin-4-ol (4.61 g) in DMF (25 mL) and add slowly to a suspension of sodium hydride (95%) (1.11 g) in DMF (25 mL) at room temperature. Heat the mixture in an oil bath at 65° C. After 30 min., add 1,2-difluorobenzene (4.56 g) and stir at 65° C. After 2 hr., partition between water and ether, dry over anhydrous sodium sulfate, evaporate to give a yellow oil (5.88 g, 70% yield). Mass spectrum (electric spray) m/z=210 (M+1); 1H NMR (CDCl3): 7.05 (m, 3H), 6.92 (m, 1H), 4.29 (m, 1H), 2.71 (m, 2H), 2.30 (s, 3H), 2.27 (m, 2H), 1.99 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:32])[N:17]([C:28]([CH3:31])([CH3:30])[CH3:29])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1.[C:33]([O:42][CH3:43])(=[O:41])[C:34]1[C:35](=[CH:37][CH:38]=[CH:39][CH:40]=1)O.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:28]([N:17]1[C:16](=[O:32])[C:15]([NH:14][CH2:13][CH2:12][O:11][C:40]2[CH:39]=[CH:38][CH:37]=[CH:35][C:34]=2[C:33]([O:42][CH3:43])=[O:41])=[C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:18]1(=[O:26])=[O:27])([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1OCCNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Temperature: 120 °C
Yield: 6.3 %

Procedure:
2-[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]ethyl 4-methylbenzenesulfonate (150 mg, 0.313 mmol) was dissolved in dry MeCN (3 mL) under nitrogen atmosphere. Methyl salicylate (52 mg, 0.345 mmol) was added followed by potassium carbonate (217 mg, 1.567 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 20 mins. Potassium carbonate was filtered off and the reaction mixture was evaporated to dryness in a vacuum centrifuge. The crude product was purified by preparative HPLC affording the title compound (9 mg, 6%). 1H NMR (CDCl3, 500 MHz): δ 1.74 (s, 9H), 3.27 (q, 2H), 3.97-4.00 (m, 5H), 6.17 (t, 1H), 6.86 (d, 1H), 7.05 (t, 1H), 7.44-7.48 (m, 4H), 7.52-7.56 (m, 2H), 7.85 (dd, 1H); 13C NMR (CDCl3, 125 MHz): δ 27.85, 43.53, 52.52, 61.69, 67.49, 107.84, 114.40, 121.12, 121.69, 125.42, 129.00, 129.85, 131.69, 132.27, 133.85, 135.56, 158.01, 159.56, 166.79; Mass Spectrum: M+H+ 459.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.[CH2:16]([NH2:26])[C:17]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][O:20][C:19]=2[CH:18]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:26][CH2:16][C:17]2[CH:25]=[CH:24][C:23]3[O:22][CH2:21][O:20][C:19]=3[CH:18]=2)=[N:4][N:3]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1ccc2c(Cl)nnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(Cl)nnc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 35 %

Procedure:
3.5 g of the 1,4-dichloro-6-nitrophthalazine prepared in the step (a) was dissolved in 100 ml of ethanol, followed by the addition thereto of 2.17 g of piperonylamine and 3 ml of triethylamine. The resultant mixture was heated under reflux for 12 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. Water was added to the residue thus obtained to give a solution. The obtained aqueous solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then subjected to vacuum concentration to remove the solvent. The residue was purified by silica gel column chromatography [n-hexane/ethyl acetate (2: 1 to 1: 1)]. Thus, 1.8 g of 1-chloro-4-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine was obtained from less polar fractions as a yellow solid and 1.2 g of 1-chloro-4-(3,4-methylene-dioxybenzyl)amino-7-nitrophthalazine was obtained from more polar fractions as a yellow solid.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.[NH3:13]>CCO>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:3]=[C:2]([NH2:13])[S:6][N:5]=1
Reactant: N
Reactant: Clc1nc(-c2ccccn2)ns1
Solvent: CCO
Product: Nc1nc(-c2ccccn2)ns1

Procedure:
A solution of 2-(5-chloro-1,2,4-thiadiazol-3-yl)pyridine in 2 M ammonia in EtOH (10 ml) was heated overnight at 70° C. Volatiles were removed by concentration under reduced pressure. Purification by chromatography on silica (eluted with 0->10% MeOH/CH2Cl2+0->1% NH4OH) gave 3-(pyridin-2-yl)-1,2,4-thiadiazol-5-amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Product: Brc1ccc2c(ccn2Cc2ccccc2)c1
Yield: 77.7 %

Procedure:
The title compound was prepared from 5-bromoindole (5.02 g, 25.6 mmol) and benzyl bromide (6.7 mL, 56 mmol), following the procedure described in Step 1 of Example 5. Purification by flash chromatography on Biotage apparatus using hexane as an eluant yielded 1-benzyl-5-bromo-1H-indole as a white solid (5.69 g, 78%), mp 93-95° C. Mass spectrum (+ESI, [M+H]+) m/z 286; 1HNMR (500 MHz, DMSO-d6): δ 7.7 (d, 1H, J=1.8 Hz), 7.55 (d, 1H, J=3.1 Hz), 7.4 (d, 1H, J=8.7 Hz), 7.15-7.30 (m, 6H), 6.45 (dd, 1H, J=3.2 Hz and 0.6 Hz), and 5.45 ppm (s, 2H). Elemental Analysis for C15H12BrN: Calculated: C, 62.96; H, 4.23; N, 4.89. Found: C, 63.36; H, 4.31; N, 4.73.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].[H-].[Na+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7](=[O:12])[C:6]2=[O:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)C(=O)N2CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A solution of 5-methoxyindoline-2,3-dione (0.5 g, 2.82 mmol) in dry DMF (7 ml), under nitrogen atmosphere, was cooled to 0° C., and sodium hydride (60% w/w dispersion in mineral oil, 0.135 g, 3.39 mmol) was added portionwise. The mixture was stirred at 0° C. for 1 hour, and tert-butyl 2-bromoacetate (0.458 ml, 3.10 mmol) was added dropwise. The reaction was then stirred at room temperature overnight. The solvent was evaporated, ethyl acetate was added, and the mixture was washed with brine. The organic layer was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (ethyl acetate:petroleum ether=8:2) to afford tert-butyl 2-(5-methoxy-2,3-dioxoindolin-1-yl)acetate (0.650 g, 2.231 mmol, 79% yield). MS/ESI+ 235.8 [MH-tert-Bu]+.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[NH:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[O:20][CH:19]=[N:18][CH:17]=1.C([O-])(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH:3]([C:15]1[NH:11][C:12]([C:16]2[O:20][CH:19]=[N:18][CH:17]=2)=[CH:13][CH:14]=1)=[O:4]
Reactant: c1c[nH]c(-c2cnco2)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: O=Cc1ccc(-c2cnco2)[nH]1
Temperature: 25 °C
Yield: 80 %

Procedure:
To an ice cooled 1 mL dimethylformamide was added 0.82 g (5.4 mmol) of phosphorus oxychloride while stirring under a nitrogen atmosphere. The mixture was stirred 20 minutes and then was added a solution of 0.60 g (4.5 mmol) of 5-(pyrrol-2-yl)oxazole in 15 mL of 1,2-dichloroethane while cooling in an ice bath. The reaction mixture was then heated under reflux for 20 minutes. After cooling to room temperature, 50 mL of chloroform was added followed by 60 mL of saturated aqueous sodium acetate. After heating under reflux for 20 minutes, the mixture was cooled to room temperature and the organic layer separated, washed with aqueous sodium carbonate and dried over anhydrous sodium sulfate. Following evaporation of the solvent at reduced pressure, the crude product was purified by column chromatography with chloroform elution to give 0.58 g (80%) of 5-(5-formylpyrrol-2-yl)oxazole as a white solid, m.p. 152°-153° C.; 1H-NMR (Acetone-d6) δ 6.68 (d, 1H, ArH), 7.09 (d, 1H, ArH), 7.61 (S, 1H, ArH), 8,22 (s, 1H, ArH), 9.57 (s, 1H, CHO).
Reaction SMILES: O=O.[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH:21]=1)[NH2:20].[H-].[Na+]>CN(C=O)C>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:15]2[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH:21]=2)[NH2:20])=[CH:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])c(N)c2)cc1

Procedure:
Compounds of Formula (I), wherein R3 is —C(O)OCH3, A is phenyl, and X and Z are oxygen, D and T are CH, M is C, Q is N(R7)p, either p or q is 1, and the other is 0, can be prepared according to the synthetic sequence shown in Scheme 1 and further detailed in the Examples section following. 4-Acetamidophenol (1) in DMF is reacted with 5-chloro-2-nitroaniline (2) in the presence of 60% NaH to provide 5-(4-acetamidophenoxy)-2-nitroaniline (3). The nitroaniline (3) is then refluxed with Na2S2O4 to provide 4-(4-acetamidophenoxy)phenylene-1,2-diamine (4). (It is understood that reduction of nitro group of (3) can be effected in many ways, for example by use of H2, Pd/C; Raney Nickel with hydrazine; SnCl4 in HCl; etc.) Diamine (4) is refluxed with 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea in ethanol and the acetylated carbamate (5) is obtained. HCl is added to deacetylate the carbamate (5) to give methyl (5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate (7). Alternatively, carbamate (7) may be prepared by refluxing 3,4,4′-triaminodiphenylether (6) with 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea and then treating with conc. HCl to give carbamate (7). Carbamate (7) is then reacted with the appropriate phenyl isocyanate (8) to give the resultant benzimidazole (9) of the present invention. It is understood that R1 and R2 are as described above. When X of Formula (I) is sulfur and Z of Formula (I) is oxygen, the final compounds are obtained by following the same procedure using a phenylthiol derivative of 1. When X of Formula (I) is sulfur, the compound thus obtained can be oxidized with MCPBA (metachloroperbenzoic acid) to give compounds containing sulfone (SO2) or sulfine (SO) as X. Also, when 3-(3-substitutedphenyl)aminocarbonylamino)phenoxy derivatives of Formula 1 are prepared, 3-acetamidophenol is utilized instead of 4-acetamidophenol.