Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(-c2cccc(C(F)(F)F)c2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
Methyl 5-bromonicotinate (168.2 mg), 3-trifluoromethylbenzeneboronic acid (165.6 mg), K3PO4 (378.5 mg) and Pd(PPh3)4 (92.2 mg) was mixed in dioxane (5 ml). To the suspension was added water (0.25 ml). And the mixture was heated to 100° C. under stirring. After 6 hours, the mixture was cooled to room temperature and was diluted with EtOAc. The insoluble material was filtered off and washed with EtOAc. The filtrate was poured into saturated aqueous solution of NaHCO3 and extracted with EtOAc. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=94/6˜50/50) to give methyl 5-[3-(trifluoromethyl)phenyl]nicotinate (190.1 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2]C1C=CC=C(OC)C=1.COC1C=CC2C(=CC(OC)=CC=2)C=1.COC1C=CC2C(=CC3C(C=2)=CC=CC=3OC)C=1.N.[Na].[NH:45]1[C:52](=[O:53])[CH2:51][C:49](=[O:50])[NH:48][C:46]1=[S:47]>C(O)C>[CH3:1][O:2][CH:51]1[C:49](=[O:50])[NH:48][C:46](=[S:47])[NH:45][C:52]1=[O:53]
Reactant: COc1cccc(OC)c1
Reactant: O=C1CC(=O)NC(=S)N1
Agent: COc1ccc2cc3cccc(OC)c3cc2c1
Agent: COc1ccc2ccc(OC)cc2c1
Agent: N
Solvent: CCO
Product: COC1C(=O)NC(=S)NC1=O

Procedure:
The first step of synthesis of fused ring bridge, ring locked dyes according to the invention is the Birch reduction of 1,3-dimethoxybenzene, 2,7-dimethoxynaphthalene or 2,8-dimethoxyanthracene using ethanol, liquid ammonia and sodium. The reduced compounds are the starting materials for the synthesis of the dyes, as shown below. ##STR15## The Birch reduction products of 1,3-dimethoxybenzene and of 2,7-dimethoxynaphthalene each react with thiobarbituric acid to form the conjugated methoxy-thiobarbituric acid dyes as shown in FIG. 13. For this reaction, no solvent is used. The reactants were melted at 145° C. for 15 min. Methanol condensing at the walls of the flask showed successful reaction. Purification was carried out by simple filtration over a short column of SiO2 with CH2Cl2. Yields were typically around 60%.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:37]=[CH:36][C:14]([O:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:17]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34]C)[CH:29]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:17]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=3)=[CH:36][CH:37]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(O)c3)ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
A solution of 1-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(3-methoxyphenyl)-6-methoxynaphthalene hydrochloride (0.500 g, 0.96 mmol) in 20 mL of anhydrous methylene chloride under N2 atmosphere was chilled in an acetonitrile-dry ice bath to −20° C. Boron tribromide (1.44 mmol) was added dropwise over 3 minutes by syringe as a 1 M solution (1.44 mL) also in methylene chloride. The resulting mixture was allowed to warm to 0° C. and stirred for 2 hours. The reaction was then poured into a stirring solution of cold saturated sodium bicarbonate (100 mL) and the crude product was extracted with ethyl acetate (4×25 mL). The organic extracts were combined, dried (magnesium sulfate), and concentrated to a oily foam. The crude free base was purified by radial chromatography using 5/95 methanol/methylene chloride. The appropriate fractions were combined and concentrated in vacuo to provide 220 mg (49%) of 1-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(3-hydroxyphenyl)-6-methoxynaphthalene as a white crystalline solid, mp 170-171° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH2:20]([O:22][CH2:23][CH2:24][O:25][C:26]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O)[CH3:21].[O-]CC.[Na+]>>[CH2:20]([O:22][CH2:23][CH2:24][O:25][C:26]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][C:27]=1/[CH:28]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1)[CH3:21]
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Reactant: CCOCCOc1c(C=O)cccc1OC
Agent: CC[O-]
Agent: [Na+]
Product: CCOCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C#N)cc2)cccc1OC
Yield: 39 %

Procedure:
The title compound was prepared by condensation of Intermediate 4 (335 mg, 1.252 mmol) with 2-(2-ethoxyethoxy)-3-methoxy-benzaldehyde (339 mg, 1.753 mmol) in presence of sodium ethoxide (170 mg, 2.506 mmol) according to the procedure described in Example 9 to yield 231 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.16 (t, J=6.6 Hz, 3H), 3.45-3.52 (m, 4H), 3.78 (s, 3H), 4.00-4.08 (m, 2H), 6.78 (d, J=15.6 Hz, 1H), 6.94-7.01 (m, 3H), 7.50-7.58 (m, 3H), 7.92 (d, J=7.8 Hz, 2H), 8.02 (d, J=4.8 Hz, 1H), 8.20 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 474.45 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:16][C:17](=[CH2:19])[CH3:18].[OH-].[Na+]>ClCCl.O>[C:17]([O:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1)([CH3:19])([CH3:18])[CH3:16]
Reactant: C=C(C)C
Reactant: OCc1ccc(CCl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OCc1ccc(CCl)cc1
Yield: 45 %

Procedure:
A 5-gallon stirred pressure reactor was charged with p-hydroxymethylbenzyl chloride (600 g, 3.83 moles) in dichloromethane (6 liters). Concentrated sulfuric acid (60 mL) was charged to the reactor. Isobutylene gas was charged to the stirred solution for 2 hours at 10 psi. The temperature of the reaction was maintained at 20°-25° C. At the end of 24 hours the reaction was about 85% complete. The reaction mixture was diluted with water and the mixture adjusted to pH 7 by addition of 25% aqueous sodium hydroxide. The dichloromethane extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was fractionally distilled on a 24 cm Vigreux column to provide 312 g (45% yield) of the desired product. The boiling point of the product was 115°-125° C. (2-3 mm Hg). 1H NMR spectral data were as follows: (CDCl3, 300 MHz): δ7.4 (s, 4H), 4.58 (s, 2H), 4.45 (s, 2H), 1.3 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10](=O)([O-:12])[O-:11].[K+].[K+].Cl>O>[OH:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: OCc1cccc(O)c1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(CO)cc1O
Temperature: 150 °C
Reaction time: 18 h

Procedure:
A mixture of 3-hydroxybenzylalcohol (10 g, 80 mmol) and potassium carbonate (33.35 g, 240 mmol) were stirred under carbon dioxide in a sealed vessel at 1500-2000 psi and 150° C. for 18 hours. The cooled residue was dissolved in water, acidified to pH 1 using concentrated hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. The product was recrystallised from cyclohexane to afford the title compound, 740 mg.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH3:14]>CC(C)=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Solvent: CC(C)=O
Product: CC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Ex-35A: To a solution of 4-acetylbenzenesulfonyl chloride in acetone (30 mL) was added ammonia (28% in water, 8.2 mL, 57.3 mmol) dropwise at 0° C. The reaction mixture was allowed to stir at 0° C. for 30 min. The precipitate was filtered and the residue was washed with water and dried in vacuo to afford 4-acetylbenzenesulfonamide as a white solid (3.54 g, 93%), mp 176–177° C. 1H NMR (DMSO-d6) δ 8.10 (d, J=9 Hz, 2H), 8.03 (d, J=9 Hz, 2H), 4.86 (brs, 2H), 2.65 (s, 3H). HRMS Calcd. for C8H9NO3S: 199.0303 (M+); Found: 199.0300.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.C1CN([P+](O[N:38]2N=[N:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(N)C=CC=CC=1N.CCN(CC)CC>CN(C=O)C>[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:45][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:6]2[C:5]3[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=3[NH:3][C:2]2=[O:1])=[CH:16][CH:15]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)c1ccc(Cn2c(=O)[nH]c3ccccc32)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(Cn2c(=O)[nH]c3ccccc32)cc1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A solution of 4-(2-Oxo-2,3-dihydro-benzoimidazol-1 -ylmethyl)-benzoic acid (0.1 mmol) in DMF (1 mL) was sequentially treated with PyBOP (0.12 mmol), 1,2-phenylenediamine (0.12 mmol) and Et3N (0.3 mmol). After stirring at 23° C. for 4 h, the reaction was filtered and the crude material was purified by HPLC to yield N-(2-Amino-phenyl)-4-(2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-benzamide. 1H NMR (400 MHz, DMSO-D6) δ ppm 4.88 (s, 2H), 5.09 (s, 2H), 6.55-6.61 (m, 1H), 6.76 (d, J=8.08 Hz, 1H), 6.93-7.04 (m, 5H), 7.14 (d, J=7.58 Hz, 1H), 7.43 (d, J=8.08 Hz, 2H), 7.93 (d, J=8.08 Hz, 2H), 9.61 (s, 1H), 11.02 (s, 1H). ESI-MS: m/z 359.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:51])[C:9]([N:11]2[C:15]3[N:16]=[C:17]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:18]=[C:19]([C:20]4[CH:21]=[N:22][C:23]([N:26](CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=[N:24][CH:25]=4)[C:14]=3[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.OCCN1CCN(C2C=CC(N(C)C(N3C4N=C(N5CCOCC5)N=C(C5C=NC(N(CC6C=CC(OC)=CC=6)CC6C=CC(OC)=CC=6)=NC=5)C=4CC3)=O)=CC=2)CC1>>[CH3:51][N:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:9]([N:11]1[C:15]2[N:16]=[C:17]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[N:18]=[C:19]([C:20]3[CH:25]=[N:24][C:23]([NH2:26])=[N:22][CH:21]=3)[C:14]=2[CH2:13][CH2:12]1)=[O:10]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)c3ccc(Br)cc3)cn2)cc1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)c3ccc(N4CCN(CCO)CC4)cc3)cn2)cc1
Product: CN(C(=O)N1CCc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21)c1ccccc1
Yield: 22.1 %

Procedure:
Using 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (4-bromo-phenyl)-methyl-amide (121 mg) obtained in Step B in Example 1-D-160 instead of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (3-bromo-phenyl)-methyl-amide, in the same manner as Step C in Example 1-D-153, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenyl}-methyl-amide was obtained. The PMB groups were removed according to Deprotection method 3, to obtain the desired compound (D-162) as a colorless solid (17.1 mg, 38%)) and the desired compound (D-163) as a colorless solid (15.4 mg, 11%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)O1.Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[C:31]3[N:33]=[C:34]([O:36][C@H:37]4[CH2:42][O:41][C@H:40]([CH2:43][OH:44])[C@@H:39]([OH:45])[CH2:38]4)[NH:35][C:30]3=[CH:29][C:28]=2[Cl:46])=[CH:23][CH:22]=1>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:46][C:28]1[CH:29]=[C:30]2[NH:35][C:34]([O:36][C@H:37]3[CH2:42][O:41][C@H:40]([CH2:43][OH:44])[C@@H:39]([OH:45])[CH2:38]3)=[N:33][C:31]2=[N:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([OH:18])([CH3:16])[CH3:17])=[CH:13][CH:14]=2)=[CH:22][CH:23]=1
Reactant: OC[C@H]1OC[C@H](Oc2nc3nc(-c4ccc(Br)cc4)c(Cl)cc3[nH]2)C[C@@H]1O
Reactant: CC(C)(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(O)c1ccc(-c2ccc(-c3nc4nc(O[C@H]5CO[C@H](CO)[C@@H](O)C5)[nH]c4cc3Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (50.4 mg, 0.192 mmol) and (2R,3 S,5R)-5-((5-(4-bromophenyl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)-tetrahydro-2H-pyran-3-ol (70 mg, 0.154 mmol) were dissolved in dioxane (600 μl) and water (600 μl). The reaction mixture was sparged with N2 with 15 min and then [1,1′-Bis(Diphenylphosphino)-Ferrocene]Dichloropalladium (II) (22.53 mg, 0.031 mmol) was added. After stirring 3 h at 80° C., the reaction mixture was diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2); and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by mass directed reverse phase HPLC eluted with acetonitrile in water containing 0.1% formic acid. The desired fractions were combined and lyophilized to give the title compound as a white solid. LC-MS: calculated for C27H28ClN3O5 509.17 observed m/e: 509.87 (M+H)+ (Rt 1.12/2 min); 1H NMR δ (ppm) (CD3OD): 7.82 (s, 1H), 7.72 (s, 4H), 7.66 (d, 2H), 7.59 (d, 2H), 5.11 (septet, 1H), 4.34 (dd, 1H), 3.88 (dd, 1H), 3.66-3.59 (m, 2H), 3.37 (t, 1H), 3.18-3.15 (m, 1H), 2.76-2.74 (m, 1H), 1.68 (q, 1H), 1.58 (s, 6H).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.C(=O)(O)[O-].[Na+].O.[Cl:31][CH2:32][CH2:33][OH:34]>S(=O)(=O)(O)O>[Cl:31][CH2:32][CH2:33][O:34][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1]
Reactant: OCCCl
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (1 g.) was dissolved in 2-chloroethanol (50 ml.) and concentrated sulphuric acid (6 drops) added to the solution. The mixture was stirred at room temperature for 1 hour, neutralised with sodium bicarbonate solution and poured into water (500 ml.). The precipitate formed was extracted into ether (2 × 100 ml.) and the combined extracts washed with water (2 × 100 ml.). The organic layer was dried over anhydrous sodium sulphate and evaporated to a yellow oil (1.5 g.) which was purified by preparative tlc using ethyl acetatepetroleum ether, 1/1 run 3 times. The main band (RF ~0.2 - 0.3) gave the title compound (640 mg.) as an off-white foam identical with a previously prepared sample.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]1([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]2[CH:27](N)C)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:27][C:19]3[N:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: CC(N)c1nc2ccccc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ncnc2c1c(I)cn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.15 g, 4.1 mmol), 1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (1.0 g, 4.1 mol) and K2CO3 (0.6 g, 4.3 mmol) in DMSO (20 mL) was stirred at room temperature overnight. Then the mixture was added H2O (50 mL) and extracted with CH2Cl2 (20 mL×3). The combined organic layers were concentrated in vacuo to give 4-chloro-5-iodo-7-(1-phenyl-1H-benzoimidazol-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.7 g, yield 85%) as brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:47][NH2:48]>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:47][NH:48]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)NCCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NCCc2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-(2-phenylethyl)-3-piperidinecarboxamide (197.7 mg, 0.431 mmol), 5 mL of EtOH, Hunig's base (0.289 mL, 1.653 mmol), and hydrazine anhydrous (0.078 mL, 2.480 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow suspension as well as some black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid and the yellow solution were carefully separated due to the black solid being heavier than the yellow solution. Water (20 mL) was added to the yellow solution, and a solid formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized using CH3CN, and the solid in the solvent was filtered, washed by EtOAc and CH3CN, and dried in vacuum. The yellow residue was dissolved in CH3OH, and purified by HPLC to afford the light yellow title compound (31 mg). LC-MS (ES) m/z=517 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.08-1.18 (m, 4H), 1.56-1.70 (m, 4H), 1.71-1.86 (m, 1H), 2.17-2.31 (m, 1H), 2.68-2.78 (m, 3H), 2.82-2.99 (m, 1H), 5.24-5.57 (m, 2H), 6.03-6.13 (m, 2H), 6.50-6.58 (m, 1H), 7.16-7.37 (m, 5H), 7.50-7.61 (m, 1H), 7.66-7.76 (m, 1H), 7.90-7.97 (m, 1H), 8.01-8.12 (m, 1H), 8.19 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:24])([CH3:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.C(O)C>[OH:24][C:7]1([CH3:23])[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1)C(C)(O)C(C(=O)O)=C2c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.8 %

Procedure:
1-Hydroxy-6-methoxy-1-methyl-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (100 mg, 0.309 mmol) prepared in Example 4 was dissolved in THF, and an excess amount of sodium hydroxide dissolved in aqueous ethanol was added thereto in such a way not to cause layer separation. The mixture was stirred for 24 hrs at RT, and the pH was adjusted to 3˜4 using 2N hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure, to obtain 63 mg of the titled compound (yield: 69%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O>C(O)(C)C.Cl.C(Cl)(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:24][C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Reactant: O=Cc1ccco1
Agent: Cl
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2cnc3ccccc3c2n1N=Cc1ccco1
Reaction time: 48 h
Yield: 93.8 %

Procedure:
A solution of 2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (1.50 g, 6.19 mmol) in 20 mL of isopropanol was treated with 2-furaldehyde (1.08 mL, 13.0 mmol) and 2 drops of concentrated HCl and heated to reflux under an atmosphere of nitrogen. After 48 h, the reaction was concentrated under reduced pressure to yield a brown oil. The oil was dissolved in 30 mL of CHCl3 and washed with 5% Na2CO3 solution, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(furan-2-ylmethylene)amine (1.86 g) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].N12CCCN=C1CCCCC2>CC(C)=O>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: CCc1ccnc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Product: CCc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)OC)c1
Temperature: 25 °C

Procedure:
A mixture of methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A, 700 mg, 1.99 mmol), 2-bromoacetyl-4-ethylpyridine* (545 mg, 2.39 mmol), potassium carbonate (1.37 g, 13.9 mmol) and acetone (20 ml) was stirred at room temperature. After stirring for 3 h, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.6 ml, 3.98 mmol) was added. The resulting mixture was stirred for an additional 19 h and then concentrated. The residue was diluted with dichloromethane (200 ml) and washed with water (100 ml×2). The organic layer was dried (MgSO4) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane/dichloromethane (1:4:1) to give the title compound including impurity. The crude product was washed with ethyl acetate to give 297 mg (42%) of the title compound as yellow solids.