Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=[C:4]([C:14](=[O:21])[C:15]1[S:19][CH:18]=[CH:17][C:16]=1[CH3:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12]>O1CCOCC1.O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:14]([C:15]1[S:19][CH:18]=[CH:17][C:16]=1[CH3:20])=[O:21])([O-:13])=[O:12]
Reactant: Cc1ccsc1C(=O)C(=CN(C)C)c1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccsc1C(=O)Cc1ccccc1[N+](=O)[O-]
Yield: 66.8 %

Procedure:
A solution of 62.0 g of β-(dimethylamino)-α-(3-methyl-2-thenoyl)-2-nitrostyrene in 565 ml of 1,4-dioxane and 115 ml of water was refluxed for 48 hr and concentrated. The residue was extracted with dichloromethane, and the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue crystallized at room temperature. Recrystallization from 95% ethanol gave 34.2 g of product, mp 85°-86.5° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].[O:18]1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1.C(#N)C>O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:25]2[CH2:26][CH2:27][C:22]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:23][CH2:24]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A mixture of 10 g (0.057 mol) of p-fluorophenyl methyl sulfone, 8.72 g (0.063 mol) of K2CO3, 24.66 g (0.172 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, and 50 ml of acetonitrile is stirred overnight at 90°-100° C. After cooling, the mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Trituration with ether affords 13.11 g (77%) of title compound as a white solid: m.p. 192°-194° C.; IR (KBr) 1588, 1369, and 1290 cm-1 ; NMR (CDCl3) δ 7.74 (m, 2H), 6.96 (m, 2H), 4.02 (s, 4H), 3.54 (m, 4H), 3.03 (s, 3H), 1.81 (m, 4H).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[NH:18][C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:31]3[C:32](=[O:36])[N:33]([CH3:35])[CH2:34][C:30]=3[CH:29]=[CH:28][N+:27]=2[O-])[C:22]([C:38]([F:41])([F:40])[F:39])=[CH:21][N:20]=1)[CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].Cl.O>CCO.[Fe]>[CH3:35][N:33]1[CH2:34][C:30]2[CH:29]=[CH:28][N:27]=[C:26]([NH:25][C:23]3[C:22]([C:38]([F:41])([F:39])[F:40])=[CH:21][N:20]=[C:19]([NH:18][C:17]4[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=4)[N:24]=3)[C:31]=2[C:32]1=[O:36]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3c4c(cc[n+]3[O-])CN(C)C4=O)n2)c(OC)c1)OCC
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3nccc4c3C(=O)N(C)C4)n2)cc1)OCC
Yield: 52.6 %

Procedure:
A solution of diethyl [3-methoxy-4-({4-[(2-methyl-5-oxido-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (Example 310, 35.0 mg, 0.0587 mmol) in EtOH (2.0 mL) was charged with iron (6.9 mg, 0.12 mmol) and heated to reflux. The reaction mixture was charged with 1 M of HCl in H2O (0.07 mL, 0.07 mmol) and stirred at reflux for 10 minutes. Additional 1 M of HCl in H2O (0.03 mL, 0.03 mmol) was added to the reaction mixture and stirred at reflux for 10 minutes. The reaction mixture was filtered through a pad of celite. The filtrate was quenched with NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to a yellow solid. The crude material was purified by silica gel chromatography on an ISCO Combi-flash Rf system using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid (17.0 mg, 50%). The material was re-purified by HPLC. The fractions containing product were combined and concentrated to yield a white solid (4.3 mg, 13%). 1H NMR (DMSO-d6, 400 MHz): δ=8.71 (br. s., 1H), 8.60 (d, J=5.05 Hz, 1H), 8.54 (s, 1H), 8.47 (br. s., 1H), 8.32 (s, 1H), 7.41 (d, J=5.05 Hz, 1H), 6.95 (s, 1H), 6.85-6.92 (m, 1H), 4.57 (s, 2H), 3.90-4.01 (m, 4H), 3.84 (s, 3H), 3.21 (s, 1H), 3.06 (s, 3H), 1.19 (t, J=6.95 Hz, 6H). MS (ES+): m/z 581.10 [MH+] (TOF, polar).
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C:11]1([CH2:24][C:25]([CH3:27])=[CH2:26])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28]O.[OH-].[Na+].O>C1COCC1>[CH2:1]([O:8][CH2:9][O:10][C:11]1([CH2:24][CH:25]([CH3:27])[CH2:26][OH:28])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: C=C(C)CC1(OCOCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)CC1(OCOCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-((benzyloxy)methoxy)-4-(2-methylallyl)piperidine-1-carboxylate (3.05 g, 8.1 mmol) in THF (50 mL) was added BH3 solution in THF (32 mL, 1 mol/L, 32.4 mmol), and the mixture was stirred at room temperature for 16 hrs. Then 30% H2O2 solution (30 mL) and 10% sodium hydroxide solution (50 mL) were added slowly to the mixture, and the mixture was stirred for another 2 hrs. The mixture was then treated with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by a standard method to give the product (1.97 g). LC-MS: m/z 394.5 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:6]([OH:7])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1.[H-].[Na+].[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1Cl>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH3:19][C:2]1([CH3:1])[CH:6]([O:7][C:23]2[N:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1
Reactant: CCC1(COCc2ccccc2)CC(O)C(C)(C)O1
Reactant: Clc1ncccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(COCc2ccccc2)CC(Oc2ncccn2)C(C)(C)O1
Yield: 96.5 %

Procedure:
1 g of the alcohol of Example 3 was added to 220 mg of a 50% suspension of sodium hydride in oil dissolved in toluene (15 ml) and the mixture was stirred under reflux for 1 hour. 2-pyrimidinyl chloride (625 mg) in 10 ml toluene was added over 30 minutes. The mixture was stirred at reflux temperature for 16 hours. The mixture was then poured into brine and extracted with diethyl ether. The ether extract was dried over magnesium sulphate and evaporated to yield a residue which was purified on a silica gel column using 8% acetone in petrol as eluant to give 1.25 g (97%) of the desired product.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[BH4-].[Na+].CC(C)=O>C(O)C>[CH3:13][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([OH:21])[CH3:20])[CH:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:10]=1[OH:11])([CH3:14])[CH3:15]
Reactant: CC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CC(O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title ketone of Example 3 (1.0 g, 0.0032 mole) was dissolved in 10 ml of absolute ethanol and the solution cooled to about 0° C. in an ice bath and 31 mg of sodium borohydride was added. The reaction wa stirred for about one hour and acetone was added. The solvents were removed in vacuo, the residue extracted twice with benzene, the organic extracts combined and dried over sodium sulfate. Removal of the solvent in vacuo gave the crude product which was chromatographed on silica to give the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=2)=[O:14])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Reactant: COC(=O)c1ccc(N)cn1
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cn1
Yield: 77 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylfuran-2-carboxylic acid (86 mg, 0.439 mmol) was condensed with methyl 5-aminopyridine-2-carboxylate, and the resultant was purified by silica gel chromatography (3% methanol-chloroform) to obtain methyl 5-[(4,5-diisopropylfuran-2-carbonyl)amino]pyridine-2-carboxylate (111 mg, 77%) as colorless prisms.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([N+:25]([O-])=O)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([NH2:25])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ncc([N+](=O)[O-])cc3OC)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC1CCC(c2ccc(-c3ncc(N)cc3OC)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of {4-[4-(3-Methoxy-5-nitro-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.14 g) in 10 Ml EtOAc was added 30 mg Pd/C. The reaction vessel was purged with hydrogen, then stirred overnight under a balloon atmosphere of hydrogen. Filtration through Celite followed by removal of solvent in vacuo afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94-1.02 (m, 1H) 1.01 (s, 3H) 1.31 (td, J=12.57, 9.98 Hz, 2H) 1.64 (d, J=11.37 Hz, 4H) 2.09 (d, J=6.82 Hz, 2H) 3.44 (s, 3H) 3.59 (s, 3H) 5.25 (s, 2H) 6.52 (d, J=2.02 Hz, 1H) 7.02 (d, J=8.34 Hz, 2H) 7.47 (d, J=2.02 Hz, 1H) 7.54 (d, J=8.34 Hz, 2H); (M+H)+355.1.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32]O)=[O:6])[CH:2]=[CH2:3].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.C(OP([CH2:59][C:60]([N:62]([CH3:64])[CH3:63])=[O:61])(OCC)=O)C.[H-].[Na+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1/[CH:32]=[CH:59]/[C:60]([N:62]([CH3:63])[CH3:64])=[O:61])=[O:6])[CH:2]=[CH2:3]
Reactant: CCOP(=O)(CC(=O)N(C)C)OCC
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C/C(=O)N(C)C
Yield: 88.1 %

Procedure:
The same operation as in Reference Example 4-1) was carried out by using (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine (the compound obtained in Reference Example 3-1); 2.00 g, 4.35 mmol), dimethyl sulfoxide (0.87 ml, 12.2 mmol), oxalyl chloride (0.56 ml, 6.5 mmol), triethylamine (3.03 ml, 21 8 mmol), 2-(diethylphosphono)-N,N-dimethylacetamide (1.17 g, 5.22 mmol) and 60% sodium hydride (174 mg, 4.35 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 40 ml, elution with hexane-ethyl acetate 1 1) to give the title compound (2.02 g, 88.1% yield)
Reaction SMILES: IC.[CH3:3][O:4][C:5](=[O:38])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=5)[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1.[C:39]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:3][O:4][C:5](=[O:38])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][CH3:39])=[CH:33][CH:32]=5)[C:22]([C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(O)cc3)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(OC)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (8 μL) is added to a mixture of {(S)-6-[(R)-4-(4-hydroxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (30 mg), K2CO3 (15 mg), and N,N-dimethylformamide (1 mL) at room temperature. The mixture is stirred at room temperature overnight. The mixture is filtered and then chromatographed (HPLC; acetonitrile/water) to give the title compound. LC (method 6): tR=1.26 min; Mass spectrum (ESI+): m/z=535 [M+Na]+.
Reaction SMILES: [Br:1][CH:2]1[C:7]([CH2:8][Br:9])=[C:6]([C:10]([O:12]C(C)(C)C)=[O:11])[N:5]2[C:17](=[O:29])[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:4]2[S:3]1=[O:30]>FC(F)(F)C(O)=O>[Br:1][CH:2]1[C:7]([CH2:8][Br:9])=[C:6]([C:10]([OH:12])=[O:11])[N:5]2[C:17](=[O:29])[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:4]2[S:3]1=[O:30]
Reactant: CC(C)(C)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(CBr)C(Br)S(=O)[C@H]12
Yield: 93.6 %

Procedure:
A solution of 5.6 g of t-butyl 2-bromo-3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide in 40 ml of trifluoroacetic acid was stirred for 15 minutes at room temperature and the solvent was removed under vacuo. Ether was added to the residue, whereafter the evaporation to dryness was repeated. After addition of ether, the crystals were collected by filtration to obtain 4.72 g of 2-bromo-3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide as a slightly yellow solid having the following characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]([C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH2:19][CH3:20])[N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]([C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH2:19][CH3:20])[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1nc(Br)sc1C(=O)OC
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(N2CC(NC(=O)OC(C)(C)C)C2)sc1C(=O)OC
Yield: 66.5 %

Procedure:
The same operation as in Example (217a) was performed using 3-tert-butoxycarbonylaminoazetidine (124 mg, 0.72 mmol), methyl 2-bromo-4-ethyl-1,3-thiazole-5-carboxylate obtained in Example (22c) (158 mg, 0.63 mmol) and diisopropylethylamine (0.21 mL, 1.20 mmol), to obtain 143 mg of the title compound as a white solid (66%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][CH2:37][O:38][CH3:39])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:40].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][CH2:37][O:38][CH3:39])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:40][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Yield: 33.3 %

Procedure:
This was prepared using the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), 5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-amine (165 mg, 0.65 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (109 mg, 33%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 1.96 (quintet, 2H), 2.40 (m, 4H), 2.47 (t, 2H), 2.72 (t, 2H), 3.35 (s, 3), 3.55 (t, 2H), 3.60 (m, 4H), 3.94 (s, 3H), 4.20 (t, 2H), 6.14 (s, 2H), 7.07 (s, 1H), 7.19 (s, 1H), 7.83 (s, 1H), 8.32 (s, 1H), 9.48 (s, 1H); Mass Spectrum: M+H+ 555/557.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[NH:7][C:8]([C:10]3[C:14]([N+:15]([O-])=O)=[CH:13][NH:12][N:11]=3)=[N:9][C:5]=2[CH:4]=1>[Pd].C(O)C.CN(C=O)C>[CH3:21][O:20][C:19]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:9][C:8]([C:10]3[C:14]([NH2:15])=[CH:13][NH:12][N:11]=3)=[N:7][C:6]=2[CH:18]=1
Reactant: COc1cc2nc(-c3n[nH]cc3[N+](=O)[O-])[nH]c2cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1OC
Yield: 53.6 %

Procedure:
A mixture of 5,6-dimethoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazole (2.08 g, 7.2 mmol) and 10% palladium on carbon (200 mg) in ethanol (150 ml) and DMF (50 ml) was hydrogenated at room temperature and pressure overnight. The reaction mixture was filtered through celite and the solvent removed in vacuo. The resulting solid was azeotroped with methanol and toluene and the solvent removed in vacuo. The crude material was columned in DCM, methanol, acetic acid, water (120:18:3:2)[DMAW120] followed by dichloromethane 90 ml, methanol 18 ml, acetic acid 3 ml, water 2 ml (90:18:3:2) (DMAW90). Product fractions were combined and the solvent removed in vacuo to yield 3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (˜1 g, ˜53%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6](=[O:7])[C:5]2[C:8]([CH3:17])=[C:9]([CH3:16])[C:10]([NH:13][CH:14]=[O:15])=[C:11]([CH3:12])[C:4]=2[O:3]1.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1COCC1>[CH2:19]([C:6]1([OH:7])[C:5]2[C:8]([CH3:17])=[C:9]([CH3:16])[C:10]([NH:13][CH:14]=[O:15])=[C:11]([CH3:12])[C:4]=2[O:3][C:2]1([CH3:18])[CH3:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1c(C)c2c(c(C)c1NC=O)OC(C)(C)C2=O
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)c2c(c(C)c1NC=O)OC(C)(C)C2(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2,2,4,5,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-6-yl)formamide obtained in Reference Example 73 (600 mg, 2.43 mmol) in THF (5 mL) was added dropwise to a solution of benzylmagnesium chloride (a 2.0 M THF solution, 10.0 mL, 20.0 mmol) in THF (20 mL) under argon atmosphere, and the mixture was stirred at room temperature for 2 hours. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain (3-benzyl-3-hydroxy-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-yl)formamide. To a mixture of said compound with trifluoroacetic acid (5 mL) was added triethylsilane (0.5 mL, 3.2 mmol) with ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and to the residue was added a saturated sodium hydrogen carbonate solution to alkalify the aqueous layer, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a solution of the obtained residue in methanol (20 mL) was added concentrated hydrochloric acid (10 ml), and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure and the residue was neutralized with a 12 N aqueous sodium hydroxide solution. After extracting with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 4:1) to obtain 440 mg (yield 62%) of the title compound. Melting point: 75-76° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[C:8]([O-])([O-:10])=[O:9].[K+].[K+].C(=O)=O.Cl>O>[Cl:1][C:2]1[N:3]=[C:4]([C:8]([OH:10])=[O:9])[NH:5][C:6]=1[Cl:7]
Reactant: Clc1nc[nH]c1Cl
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1nc(Cl)c(Cl)[nH]1
Temperature: 200 °C
Reaction time: 10 h
Yield: 75.1 %

Procedure:
A mixture of 137 g (1 mol) of 4,5-dichloroimidazole, 414 g (3 mol) of K2CO3 and 1,000 ml of carbon dioxide was stirred in an autoclave at 200° C. under autogenous pressure for 10 hours. The solid output was pulverized, suspended in 2 1 of water and brought to pH 3-4 with concentrated hydrochloric acid while being cooled with ice. The resulting precipitate was filtered off and recrystallized from water to give 136 g (75%) of 4,5-dichloroimidazole-2-carboxylic acid (Compound No. 1); mp. 240° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][C:11]([CH3:16])=[CH:12][C:13](O)=[O:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:10])[O:9]2)=[CH:7][CH:8]=1
Reactant: COc1cccc(O)c1
Reactant: CC(C)=CC(=O)O
Product: COc1ccc2c(c1)OC(C)(C)CC2=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
The title compound was synthesized by referring to Chem. Pharm. Bull., 1977, 25, 2788. To 3-methoxyphenol (8.5 g) and 3,3-dimethylacrylic acid (7.5 g) was added polyphosphoric acid (80 ml), and the solution was stirred for 2 hours at 100° C. The reaction mixture was poured into an ice water, the solution was stirred, and then extracted with diethyl ether, then sequentially washed with an aqueous solution of 2N sodium hydroxide, water and brine, dried over anhydrous magnesium sulfate, then filtered through NH silica gel, and the solvent was evaporated in vacuo. The residue was washed with a hexane-diethyl ether system to provide the title compound (10.6 g).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:19]=[C:18]([C:28]([O:30]CC)=O)[C:14]=4[NH:15]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH3:33].CO>>[N:1]1([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:19]=[C:18]([C:28]([NH2:33])=[O:30])[C:14]=4[NH:15]3)=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1nc(-c2ccccc2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Reactant: N
Solvent: CO
Product: NC(=O)c1nc(-c2ccccc2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 135 °C

Procedure:
Ethyl 7-(morpholine-4-carbonyl)-3-phenyl-9H-pyrido[3,4-b]indole-1-carboxylate (15 mg, 0.035 mmol) and 7N NH3/MeOH (1.5 mL, 10.50 mmol) were mixed in a sealed microwave tube and heated in microwave at 135° C. for 3.5 hrs. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 401.07 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.83 (s, 1H), 9.07 (s, 1H), 8.43 (m, 4H), 7.89 (s, 1H), 7.84 (s, 1H), 7.53(t, 2H, J=7.6), 7.42 (t, 1H, J=7.3), 7.32 (dd, 1H, J=7.9, 1.5), 3.67-3.43 (bm, 8H).