Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH:19]([N:22]1[C:26]([C:27]2[N:36]=[C:35]3[N:29]([CH2:30][CH2:31][O:32][C:33]4[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][C:34]=43)[CH:28]=2)=[N:25][CH:24]=[N:23]1)([CH3:21])[CH3:20]>C(Cl)Cl>[CH:19]([N:22]1[C:26]([C:27]2[N:36]=[C:35]3[C:34]4[CH:37]=[C:38]([S:41]([N:8]5[CH2:9][CH2:10][CH2:11][C@H:7]5[CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)(=[O:43])=[O:42])[CH:39]=[CH:40][C:33]=4[O:32][CH2:31][CH2:30][N:29]3[CH:28]=2)=[N:25][CH:24]=[N:23]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCC[C@H]3CN3CCCC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-pyrrolidin-1-ylmethylpyrrolidine (36 mg, 0.23 mmol) and NEt3 (54 μL, 0.39 mmol) in DCM (5 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (64 mg, 0.08 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 16 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% 2M NH3/MeOH in DCM then C18, gradient 15-40% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 123 (22 mg, 56%). LCMS: RT 2.90 min [M+H]+ 512.3. 1H NMR (DMSO, 400 MHz): δ 9.01 (1H, d, J=2.40 Hz), 7.95 (1H, s), 7.82 (1H, s), 7.77 (1H, dd, J=8.65, 2.41 Hz), 7.26 (1H, d, J=8.65 Hz), 5.90-5.89 (1H, m), 4.61-4.60 (4H, m), 3.79-3.69 (1H, m), 3.42-3.41 (1H, m), 3.30-3.24 (1H, m), 2.76 (1H, dd, J=12.12, 4.10 Hz), 2.65-2.62 (5H, m), 1.80-1.79 (7H, m), 1.67-1.54 (1H, m). 1.59 (3H, d, J=6.62 Hz), 1.57 (3H, d, J=6.58 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[CH2:26][CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[CH:30]=[N:29][N:28]([CH2:27][CH2:26][C:25]4[CH:42]=[CH:43][CH:44]=[C:23]([F:22])[CH:24]=4)[CH:32]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(CCc3cccc(F)c3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Yield: 35.39 %

Procedure:
Using similar reaction conditions as described in step-i of example-1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (200 mg, 0.41 mmol) was coupled with 1-(3-fluorophenethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 64B) (172 mg, 0.54 mmol) using sodium carbonate (130 mg, 1.23 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.020 mmol) in toluene/ethanol/water (20/10/5 ml) to afford 80 mg (35.39% yield) of the pure product after column purification using 30% ethyl acetate in hexane as eluent. MS: m/z=539.1 (M+1).
Reaction SMILES: [NH2-].[Li+].[CH2:3]([OH:6])[CH:4]=[CH2:5].C[O:8][C:9](=O)[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=1.C1(C)C=CC=CC=1>C(O)(=O)C>[CH2:3]([O:6][C:9](=[O:8])[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:19])([CH3:21])[CH3:20])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=1)[CH:4]=[CH2:5]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CCO
Agent: [Li+]
Agent: [NH2-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 150 °C

Procedure:
0.2 g of lithium amide and in the course of 5 hours 38 g of allyl alcohol are added at 150° C. under nitrogen to 146 g of 3-(3,5-di-t-butyl-4-hydroxyphenyl)-propionic acid methyl ester. After completion of the addition, stirring is maintained at 150° C. for a further 10 hours. The brownish reaction mixture is cooled to about 100° C., and 150 ml of toluene, 0.5 g of concentrated acetic acid and 10 g of "Celite Hyflow Supercel" (product of Johns Manville Corp., USA) are added. There is thus obtained, after filtration and then removal of the solvent in vacuo, the title compound in crystalline form, m.p. about 40° C.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:9]1[CH2:13][CH2:12][C:11](=O)[CH2:10]1.O>C(O)(=O)C>[S:9]1[C:10]2[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[NH:7][C:11]=2[CH2:12][CH2:13]1
Reactant: NNc1ccccc1
Reactant: O=C1CCSC1
Solvent: CC(=O)O
Solvent: O
Product: c1ccc2c3c([nH]c2c1)CCS3
Temperature: 80 °C
Yield: 48.4 %

Procedure:
To a solution of phenylhydrazine (5.0 g, 46 mmole) in acetic acid (50 ml) was added dihydro-thiophen-3-one (4.72 g, 46 mmole) at room temperature. Following an exothermic reaction, the temperature was maintained at 80° C. for 2 h. The reaction mixture was poured into water (300 ml) and the precipitate was filtered. Purification on a short column of aluminum oxide (activity II, 6% water) using t-butylmethylether as the eluting solvent gave pure 3,4-dihydro-2H-thieno[3,2-b]indole as a yellow solid (3.9 g, 48% yield), m.p. 152-155° C. (lit. m.p. 153° C., WO01/12603) Step 2
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:19])[S:18][C:12]2=[N:11][C:10]=1[C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C:26](=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>C1COCC1>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:26](=[O:35])[CH2:25][NH:24][C:20]([C:10]2[N:11]=[C:12]3[S:18][C:17]([CH3:19])=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:21])=[CH:33][CH:32]=1
Reactant: NCC(=O)Cc1ccc(F)cc1
Reactant: Cc1cn2c(=O)c(OCc3ccccc3)c(C(=O)O)nc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Cc1cn2c(=O)c(OCc3ccccc3)c(C(=O)NCC(=O)Cc3ccc(F)cc3)nc2s1
Reaction time: 8 h

Procedure:
To a solution of the product of example 1 (2.4 mmol) in THF (10 ml) was added compound 1-amino-3-(4-fluoro-phenyl)-propan-2-one hydrochloride (1.0 g, 4.9 mmol), EDCI.HCl (560 mg, 2.9 mmol), HOBt (400 mg, 2.9 mmol) and TEA (1 g, 9.9 mmol), successively at room temperature. The mixture was stirred overnight, after which saturated sodium bicarbonate was added and then extracted with ethyl acetate. The extracts were combined, washed with brine, and then dried over sodium sulfate. The product was purified by column chromatography to give the desired product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N:15]([CH2:26][CH3:27])[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C.C(C[CH2:31][N:32]1[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]1)#N>O1CCCC1.O>[OH:37][C@@H:34]1[CH2:35][CH2:36][N:32]([CH2:31][CH2:27][C:26]2[NH:15][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[CH2:33]1
Reactant: N#CCCN1CC[C@@H](O)C1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)[nH]c(CCN3CC[C@@H](O)C3)cc12
Temperature: -78 °C
Yield: 22.9 %

Procedure:
Diisopropylamine (122 mL) was dissolved in tetrahydrofuran (400 mL), and n-butyllithium (1.56 mol/L) (534 mL) was added dropwise to the solution under ice-cooling. The mixture was stirred under ice-cooling for 30 min, and then cooled to −78° C. A solution (150 mL) of N,N-diethyl-2,3-dimethylbenzamide (85.4 g) in tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at −78° C. for 0.5 hr. The reaction mixture was cooled to −78° C. and a solution (150 mL) of (R)-1-(2-cyanoethyl)-3-hydroxypyrrolidine (53 g) in tetrahydrofuran was added dropwise to the mixture. The reaction mixture was allowed to warm to room temperature. After the completion of the reaction, water was added to the reaction mixture and the organic layer was separated and concentrated. The residue was dissolved in chloroform and the solution was washed with saturated brine and dried over magnesium sulfate. The organic layer was extracted with 1N hydrochloric acid, and the layer was basified. The aqueous layer was extracted with chloroform and the extract was dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography to give (R)-3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (23.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][CH3:24])[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1CC
Temperature: 25 °C
Reaction time: 72 h
Yield: 103.6 %

Procedure:
A mixture of ethyl 5-chloro-1H-indole-2-carboxylate (500 mg, 2.17 mmol), potassium carbonate (450 mg, 3.25 mmol), iodoethane (260 μL, 3.25 mmol) and N,N-dimethylformamide (10.8 mL) was stirred at room temperature for 3 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water three times, and the organic layer was filtered through diatomaceous earth, followed by silica gel, and then the filtrate was concentrated under reduced pressure to give ethyl 5-chloro-1-ethyl-1H-indole-2-carboxylate (566 mg, 100%) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH:14]1([C:17]#[CH:18])[CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C=O)C.C1(C)C=CC=CC=1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:5]1[CH:4]=[CH:3][C:2]([C:18]#[C:17][CH:14]2[CH2:16][CH2:15]2)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C#CC1CC1
Reactant: CCOC(=O)c1cc(Br)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C#CC2CC2)ccc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
To a solution of ethyl 5-bromo-2-chlorobenzoate (1.9 g) in DMF (12 mL), toluene (0.3 mL), cyclopropylacetylene (714 mg), copper iodide (275 mg), dichloro bis(triphenylphosphine)palladium (1.01 g) and triethylamine (20.1 mL) were added, and the mixture was degassed, stirred at 100° C. under argon atmosphere for 8 hours, and then the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The insoluble material was filtered off on celite. The mother liquor was washed with brine, dried over magnesium sulfate and concentrated. By purification on column chromatography, ethyl 2-chloro-5-(cyclopropylethynyl)benzoate (1.86 g) was obtained as brown oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[S:21][C:13]3=[N:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[N:12]3[CH:11]=2)[C:5]=1[CH3:22])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[S:21](=[O:28])[C:13]3=[N:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[N:12]3[CH:11]=2)[C:5]=1[CH3:22])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1ccnc(-c2cn3c(nc4ccccc43)s2)c1C
Solvent: ClCCl
Product: CCSc1ccnc(C2=Cn3c(nc4ccccc43)S2=O)c1C

Procedure:
A solution of 2-(4-ethylthio-3-methylpyrid-2-yl)-thiazolo[3,2-a]benzimidazole (0.01 mole) is dissolved in CH2Cl2 solution (100 ml) at 0° C. and treated with m-chloroperoxybenzoic acid (0.01 mole) for 0.5 hours. The solution is then washed with sodium carbonate solution and dried (MgSO4). Purification by chromatography on silica gives the title compound.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[CH2:20]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:20]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:30])=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Product: CCCCCc1ccc(C(=O)NC2N=C(c3ccccc3)c3ccccc3NC2=O)cc1

Procedure:
The procedure of Example 134 was carried out using 3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg, 0.156 mmole) in place of 1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 4-n-pentylbenzoyl chloride (32.9 mg, 0.156 mmole) in place of p-trifluorobenzoyl chloride. The product was chromatographed on silica gel (15%, (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo and crystallized from Et2O to give the title compound which was dried in vacuo at 82° C.: (m.p. 203°-205° C.).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][C:8]=2[C:35](OCC)=[O:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.CCOCC.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][C:8]=2[CH2:35][OH:36])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1NC1CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: CCOCC
Product: OCc1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1NC1CCCC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a cold (−78° C.) solution of ethyl 7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylate (50 mg, 0.095 mmol) in dichloromethane (1 mL) was added diisobutylaluminum hydride (490 μL, 1.0 M in hexanes, 0.49 mmol). The reaction mixture was stirred at −78° C. for 2 hours then poured into a stirring mixture of ether and aqueous Rochelle's salt (sodium potassium tartrate) solution. The resultant mixture was stirred at room temperature for 16 hours. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. Concentration followed by flash chromatography on silica (29:1 dichloromethane:methanol) provided [7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo-[1,5-a]pyridin-6-yl]methanol (27 mg, 59%) as a green solid. Rf 0.26 (29:1 dichloromethane:methanol); 1H NMR (300 MHz, CDCl3): δ 7.99 (d, 1H), 7.70 (d, 1H), 7.61 (m, 2H), 7.23 (d, 1H), 7.13 (t, 2H), 6.29-6.24 (m, 2H), 5.08 (d, 1H), 4.79 (s, 2H), 4.47 (broad, 1H), 4.29 (m, 1H), 2.09-1.99 (m, 4H), 1.85-1.48 (m, 12H); MS m/z 487 (M+1).
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:19]([O:33][CH3:34])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12]([I:14])[CH:13]=[C:8]2[N:7]=1)C.[OH-].[K+]>C(O)CO.O.[Cl-].[Na+].O>[I:14][C:12]1[CH:13]=[C:8]2[N:7]=[C:6]([NH2:5])[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[C:19]([O:33][CH3:34])[CH:18]=3)[C:9]2=[N:10][CH:11]=1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)nc2)c(OC)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(I)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 12 h
Yield: 56.1 %

Procedure:
To a stirred solution of ethyl(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (Example 3-36-2) (0.42 g, 0.71 mmol) in ethylene glycol (6 mL) and water (1 mL) was added potassium hydroxide (0.197 g, 3.51 mmol). The resulting mixture was heated to 100° C. After 12 h, the mixture was allowed to cool to room temperature and was diluted with brine (40 mL). The mixture was extracted with ethyl acetate (3×40 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. Chromatographic purification of the residue (silica gel, 3% methanol in dichloromethane elute) afforded 0.206 g (56%) of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.Cl[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15].CC(C)([O-])C.[K+]>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)CCl)cc1
Reactant: COc1ccc([N+](=O)[O-])cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
A mixture of 15.4 g (0.1 mol) of 6-methoxy-3-nitropyridine and 20.4 g (0.1 mol) of 1-chloromethane-sulfonyl-4-methyl-benzene is dissolved in 100 mL of DMF and cooled to 5 C. To this solution is added, dropwise, 100 mL (0.1 mol) of a 1M solution of potassium t-butoxide in THF, keeping the temperature ≦10 C. The dark reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is evaporated to remove the THF, and to the remaining solution is added 100 mL of water. A dark brown precipitate formed which is collected by filtration. This solid is triturated with isopropyl ether for 1 hour and refiltered to yield 12 grams of 6-methoxy-3-nitro-2-(toluene-4-sulfonylmethyl)-pyridine. 1H NMR (CDCl3) δ 8.25 (d, 1H), 7.60 (m, 2H), 7.30 (m, 2H), 6.80 (d, 1H), 5.10 (s, 1H), 3.75 (s, 3H), 2.40 (s, 3H). Mass Spectrum: m/e=323.1 (p+1), TLC (CDCl3) Rf=0.45 Step 2:
Reaction SMILES: O1CCC[CH2:2]1.[C:6]([O:17]C)(=O)[C:7]1[CH:15]=[C:13]([OH:14])[C:11]([OH:12])=[C:9]([OH:10])[CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>C(OCC)(=O)C.O>[OH:10][C:9]1[CH:8]=[C:7]([CH:15]=[C:13]([OH:14])[C:11]=1[O:12][CH3:2])[CH2:6][OH:17]
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(O)cc(CO)cc1O
Temperature: 62.5 °C
Reaction time: 6 h
Yield: 36.6 %

Procedure:
Next, a tetrahydrofuran solution (4 mL) with 4-methoxy form (560 mg, 2.8 mmol) with methyl gallate was dropped carefully to a tetrahydrofuran (THF) solution (6 mL) with lithium aluminum hydride (469 mg, 12.4 mmol) in an ice bath (0° C.). Then, the mixture was stirred for six hours at 60 to 65° C., ethyl acetate and a 10% sulfuric acid aqueous solution were added to the mixture, and then the reaction was stopped. Purified water was added to the reaction liquid, extraction was performed with the ethyl acetate, and the separated ethyl acetate layer was washed with saturated saline and dehydrated by sodium sulfate. After concentration, the extract liquid was purified by silica gel column chromatography (solvent: chloroform-methanol (50:1, v/v)→chloroform-methanol (50:3 , v/v)) and a reductant, that is, synthetic 3,5-dihydroxy-4-methoxybenzyl alcohol of 175.9 mg (yield: 36.6%) was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14]C)=O.[CH3:16][NH:17][C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][N:17]1[C:12](=[O:14])[C:3]2[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[NH:20][C:18]1=[O:19]
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Reactant: CNC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc2[nH]c(=O)n(C)c(=O)c2c1
Temperature: 100 °C
Reaction time: 48 h
Yield: 78.9 %

Procedure:
To a solution of dimethyl 4-bromoisophthalate (0.25 g, 0.92 mmol) and methylurea (88.2 mg, 1.19 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (0.60 g, 1.83 mmol). 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (53.0 mg, 0.092 mmol) was then added followed by tris(dibenzylideneacetone)dipalladium (0) (42 mg, 0.046 mmol). The reaction mixture was heated to 100° C. and stirred for 2 d. The mixture was then cooled to rt and concentrated. Water was added and the remaining solid was filtered. The collected solid was then washed with DCM (3×) to afford methyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate (0.17 g, 80%). LC-MS: (FA) ES+ 235; 1H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.16 (dd, J=8.6, 2.0 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 3.87 (s, 3H), 3.26 (s, 3H).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH2:31][O:32][CH3:33])=[CH:27][CH:28]=3)[O:23][CH2:22][C:21]2([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:37][CH:36]=2)[CH3:34])=[CH:12][CH:11]=1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C(OCC)(=O)C>O1CCCC1>[OH:5][CH2:6][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH2:31][O:32][CH3:33])=[CH:27][CH:28]=3)[O:23][CH2:22][C:21]2([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:39][CH:40]=2)[CH3:34])=[CH:12][CH:11]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCc2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCc2ccc(OCCO)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 4-{4-[4-(t-butoxycarbonylmethyloxy)phenyl]-1-butyl}-7-methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-methylchroman (744 mg, 1.226 mmol) in dry tetrahydrofuran (10 mi) was added lithium aluminum hydride (71.8 mg, 1.89 mmol) at 0° C. and stirred for 4 h at the room temperature. When the reaction was completed, 17% sodium hydroxide solution was added to the reaction solution until the white precipitate appeared, and then added ethyl acetate to the reaction mixture. The resulting mixture was filtered over celite and washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (658 mg, yield: quant.) as a colorless oil. The resulting compound was used in the next reaction without purification.