Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:20])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: NC(=S)c1ccc(F)cc1
Temperature: 25 °C
Yield: 146.8 %

Procedure:
4-Fluorobenzamide (5.0 g, 35.9 mmol) in benzene (100 ml) is added Lawesson's reagent (7.27 g, 18.0 mmol) and the resulting solution is heated to reflux for 1 hour. The solution is cooled to room temperature, concentrated and water (150 ml) added. The mixture is heated to reflux for 3 hours, and cooled to room temperature. The precipitate is filtered and dried under vacuum to yield 4-fluorothiobenzamide as a yellow solid (4.1 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[NH:1]([C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1)[C:19]([CH3:20])=[O:21]
Reactant: COC(=O)c1ccc(Cc2ccc(N)cc2)cn1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(Cc2ccc(NC(C)=O)cc2)cn1

Procedure:
One gram of methyl 5-(4-aminobenzyl)picolinate were heated together with 10 ml. of acetic anhydride under reflux for two hours. The reaction mixture was concentrated under reduced pressure. The residue was added with n-hexane to form crystals. The crystals were then recrystallized from a solvent comprising a mixture of chloroform/n-hexane to obtain 0.8 g of methyl 5-(4-acetaminobenzyl)-picolinate of a melting point of 175°-177° C.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[H-].[Na+].[C:8]([C:10]1[CH:23]=[CH:22][C:13]([CH2:14][N:15]2[C:19]([CH2:20][OH:21])=[CH:18][N:17]=[CH:16]2)=[CH:12][CH:11]=1)#[N:9].O>C1COCC1.CCOC(C)=O>[C:8]([C:10]1[CH:23]=[CH:22][C:13]([CH2:14][N:15]2[C:19]([CH2:20][O:21][CH2:2][C:3]([OH:5])=[O:4])=[CH:18][N:17]=[CH:16]2)=[CH:12][CH:11]=1)#[N:9]
Reactant: O=C(O)CBr
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(Cn2cncc2COCC(=O)O)cc1

Procedure:
A solution of 2-bromoacetic acid in THF at room temperature is treated with excess sodium hydride for 15 minutes. To this mixture is added 1-(4-cyanobenzyl)-5-(hydroxymethyl)imidazole (Example 1) and the mixture is then heated. Upon cooling, the mixture is poured into H2O and EtOAc, extracted with EtOAc (3×), washed with brine, dried (MgSO4), filtered and evaporated to give the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH:33]([N:36]([CH3:46])[C:37](=[O:45])[CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([CH3:35])[CH3:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:42]3[CH2:43][CH2:44][N:39]([CH2:38][C:37]([N:36]([CH:33]([CH3:35])[CH3:34])[CH3:46])=[O:45])[CH2:40][CH2:41]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)N(C)C(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C(C)C)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide dihydrochloride to give 2-{4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-isopropyl-N-methyl-acetamide in an analogous manner as described in example 1. LR-MS: 642.3 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:15]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:38].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13]([C:14]1[CH:19]=[N:18][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:15]=1)=[O:38])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)COCCCCSc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)COCCCCS(=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 2 h
Yield: 40 %

Procedure:
While stirring under ice cooling, to a solution of 350 mg of 2-{4-[(5,6-diphenylpyrazin-2-yl)thio]butyloxy}acetic acid tert-butyl ester obtained in Example 34 in 5 ml of chloroform, 191 mg of 70% m-chloroperoxybenzoic acid was added, followed by stirring for 2 hours. The reaction solution was combined with 20 ml of a 0.2N sodium hydroxide solution, extracted with chloroform and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 145 mg of the desired compound as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH3:14])[S:11][C:10]=2[C:15](OC)=[O:16])=[CH:5][CH:4]=1)[CH3:2].CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([CH3:14])[S:11][C:10]=2[CH2:15][OH:16])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2cc(C)sc2C(=O)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1ccc(-c2cc(C)sc2CO)cc1
Temperature: 0 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-(4-ethylphenyl)-5-methylthiophene-2-carboxylate (1.5 g, 5.76 mmol), anhydrous ether (50 mL). This was followed by the addition of a solution of LiAlH4 (1 M in THF, 7.9 mL, 7.86 mmol) in tetrahydrofuran dropwise with stirring at 0° C. The resulting solution was stirred for 2.0 h at 25° C. The reaction progress was monitored by LCMS/TLC (ethyl acetate/petroleum ether=1:6). The reaction was then quenched by the addition of 10 mL of water and 5 mL of 2N HCl. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 1.26 g (94%) of (3-(4-ethylphenyl)-5-methylthiophen-2-yl)methanol as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][S:12](=[O:17])(=[O:16])[N:13]([CH3:15])[CH3:14])[C:8]([CH3:18])=[CH:7][C:6]=1[S:19]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[OH:30][C:31]1[CH2:36][C:35]([CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=2)([CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[O:34][C:33](=[O:55])[CH:32]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CO.C(Cl)(Cl)Cl>[C:1]([C:5]1[C:6]([S:19][C:32]2[C:33](=[O:55])[O:34][C:35]([CH2:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=3)([CH2:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([OH:54])=[CH:52][CH:53]=3)[CH2:36][C:31]=2[OH:30])=[CH:7][C:8]([CH3:18])=[C:9]([O:11][S:12](=[O:16])(=[O:17])[N:13]([CH3:15])[CH3:14])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(CCc2ccc(O)cc2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OS(=O)(=O)N(C)C)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(CCc3ccc(O)cc3)OC2=O)c(C(C)(C)C)cc1OS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer were added toluene-4-thiosulfonic acid S-(2-tert-butyl-4-dimethylsulfamoyloxy-5-methyl-phenyl) ester (prepared in Example UUU; 0.128 g, 0.280 mmol), 4-hydroxy-6,6-bis-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example PP; 0.100 g, 0.280 mmol), K2CO3 (0.154 g, 1.12 mmol), and DMF (8 mL), as described in General Method 9. The slurry was stirred at room temperature overnight. After standard work-up, the residue was submitted to flash chromatography (97% CHCl3 :3% MeOH) to yield the title compound, m.p. 139° C. 1H NMR (CDCl3) δ 1.53 (s, 9 H), 1.91 (s, 3 H), 2.11 (m, 4 H), 2.65 (m, 4 H), 2.86 (s, 2 H), 2.98 (s, 6 H), 4.80 (br s, 2 H), 6.72 (s, 1 H), 6.73 (d, 4 H), 6.98 (d, 4 H), 7.27 (s, 1 H).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11](=[O:32])[C@@H:12]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1SC2(CC[C@@]3(C)C(CC[C@@H]4C3=CC[C@@]3(C)[C@H]4CC[C@@H]3C(=O)COC(=O)C3C=CC=CC=3)=C2)SC1>C(Cl)(Cl)Cl>[C:1]([O:9][CH2:10][C:11](=[O:32])[C@@H:12]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C:26](=[CH:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)COC(=O)c1ccccc1
Agent: C[C@]12CCC3(C=C1CC[C@@H]1C2=CC[C@]2(C)[C@@H](C(=O)COC(=O)c4ccccc4)CC[C@@H]12)SCCS3
Solvent: ClC(Cl)Cl
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)[C@@H](C(=O)COC(=O)c3ccccc3)CC[C@@H]12
Yield: 42 %

Procedure:
The process described for the preparation of 4-pregnene-3,20-dione-21-ol benzoate (see the further-conversion of the product described in Example 4) is followed by using 4.97 g (9.7 mmoles) of 21-benzoyloxy-4,9(11)-pregnadiene-3,20-dione-3-ethylenedithioacetal as starting material [prepared as described in the preceding Step (a)], except that the crude product is not subjected to chromatography, but it is recrystallized from ethyl acetate under purifying with activated carbon to give 1.8 g (42% yield) of the aimed product, m.p.: 176°-177° C., [α]D =+175.1° (c=1 in chloroform).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:14]#[N:15])=[C:8]([C:10](=[O:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1.[H-].[Na+]>CN(C)C(=O)C>[C:33]([O:32][C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:6]2[C:7]([C:14]#[N:15])=[C:8]([C:10](=[O:13])[CH2:11][CH3:12])[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:19][CH:20]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCCCc1nc(C(=O)CC)c(C#N)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C(=O)CC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 86.8 %

Procedure:
Following a procedure similar to that described in Example 45(a) but using 0.923 g of 2-butyl-4-propionylimidazole-5-carbonitrile (prepared as described in Preparation 25), 1.56 g of t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate and 196 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 20 ml of N,N-dimethylacetamide, 1.84 g of the title compound were obtained as a viscous oil.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[Li]CCCC.[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20](S(CC)(=O)=O)[CH:19]=[C:18]2[O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>O1CCCC1>[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:19]=[C:18]2[O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1
Reactant: CCS(=O)(=O)c1cc(OCc2ccc(OC)cc2)c2cccc(Cl)c2n1
Reactant: NCC(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(NCC(F)(F)F)nc3c(Cl)cccc23)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 66.8 %

Procedure:
In a pre-dried 3-necked round bottom flask was dissolved 2,2,2-trifluoro-ethylamine (91 mg, 0.92 mmol, 1.2 equiv) in dry tetrahydrofuran (0.5 mL), under a nitrogen atmosphere. The flask was cooled down to −78° C. and 2.5M n-BuLi in hexanes (428 μL, 1.07 mmol, 1.4 equiv) was added via syringe. The mixture was stirred for 5 minutes then gradually warmed to 0° C. At this point, 8-chloro-2-ethanesulfonyl-4-(4-methoxy-benzyloxy)-quinoline (300 mg, 0.766 mmol, 1 equiv) in a solution of THF was slowly added. The mixture was stirred for 17 h at room temperature then quenched with brine and extracted into dichloromethane. The organic layer was dried over MgSO4 and concentrated down in vacuo to afford [8-chloro-4-(4-methoxy-benzyloxy)-quinolin-2-yl]-(2,2,2-trifluoro-ethyl)-amine (203 mg, 67% yield). LCMS found 397.11 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:11](N)[CH:10]=1)([O-:8])=[O:7].S([O-])([O-])=[O:26].[Na+].[Na+]>O>[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:11]([OH:26])[CH:10]=1)([O-:8])=[O:7]
Reactant: O=S([O-])[O-]
Reactant: Nc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2O)cc1
Reaction time: 2 h
Yield: 150.4 %

Procedure:
In a beaker, a mixture of 15.0 mL water and 11.0 mL concentrated sulfuric acid was added to 13.0 g 4,4'-dinitro-2-aminobiphenyl, and agitation was carried out for 2 h while heating, whereupon 26.5 g crushed ice were added. An aqueous solution of 3.51 g sodium sulfite was then added dropwise while on an ice bath, and mixing was carried out for 10 min, whereupon the mixture was allowed to stand for a few minutes. A solution produced by adding 33.4 mL concentrated sulfuric acid to 25 mL water was then boiled, and into this was slowly dropped the reaction mixture indicated above. After continuing boiling for 5 min, the solution was poured into a beaker on an ice bath. The product was then suction-filtered, and the filtrate cake was purified using column chromatography to obtain 10.9 g 4,4'-dinitro-2-hydroxybiphenyl (yield 83.9%) in the form of a yellow-brown powder. The boiling point of the product was 220°-222° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)O[C@@]2(OC[C@H]3OC(C)(C)O[C@H]3C2=O)C[O:21]1.C([O-])([O-])=O.[K+].[K+].CC(O)=O.OOS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[O:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)O[C@@H]2CO[C@]3(COC(C)(C)O3)C(=O)[C@@H]2O1
Reactant: Clc1ccccc1/C=C/COCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Product: Clc1ccccc1[C@H]1O[C@@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 56.8 %

Procedure:
To a solution of (E)-1-(3-(benzyloxy)prop-1-enyl)-2-chlorobenzene (Preparation example 367, 4.16 g, 18.58 mmole) and 1,2;4,5-di-O-isopropylidene-β-D-erythro-2,3-hexodiulo-2,6-pyranose (5.76 g, 22.30 mmole) in DME-DMM (3:1, v/v) (185 mL) was added buffer (0.2M K2CO3—AcOH in 4×10-4 aq. EDTA, buffer pH=8.0) (185 mL) and Bu4NHSO4 (0.26 g, 0.75 mmole). After the mixture was cooled to 0° C., a solution of Oxone (15.76 g, 25.64 mmole) in 4×10-4 aq. EDTA (100 mL) and a solution of K2CO3 (13.6 g, 98.47 mmole) in 4×10-4 aq. EDTA (100 mL) were added dropwise separately over a period of 3.5 hr via a syringe pump at 0° C. The reaction mixture was stirred for 14 hr at 0° C. The reaction mixture was quenched with H2O then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with H2O then dried over MgSO4 and evaporated under reduced pressure The crude compound was purified by silica ge column to produce the title compound (2.9 g, 56%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].FC(F)(F)S(O)(=O)=O.[CH3:13][C:14]1([CH3:32])[C:18]2[N+:19]([O-:29])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[N:22][C:17]=2[C:16]([CH3:31])([CH3:30])[O:15]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:13][C:14]1([CH3:32])[C:18]2[N+:19]([O-:29])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:1]([O-:4])=[O:2])[CH:24]=3)[N:21]=[N:22][C:17]=2[C:16]([CH3:31])([CH3:30])[O:15]1
Reactant: CC1(C)OC(C)(C)c2c1nnc(-c1ccccc1)[n+]2[O-]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OC(C)(C)c2c1nnc(-c1cccc([N+](=O)[O-])c1)[n+]2[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.2 ml (0.005 mole) of fuming nitric acid and 1.5 grams (0.01 mole) of trifluoromethanesulfonic acid in 15 ml. anhydrous methylene chloride, after allowing the resulting mixture to be stirred for 1 hour at 25°C., there is added dropwise maintaining the temperature at -30°C., 0.542 grams (0.002 mole) of 5,7-dihydro-5,5,7,7-tetramethyl-3-phenylfuro [3,4-e]-as-triazine-4-oxide in 15 ml. of anhydrous methylene chloride. The resulting heterogeneous mixture is stirred at 25°C. for 72 hours, poured onto ice, and neutralized with solid sodium bicarbonate. The organic layer is removed and the aqueous phase extracted several times with methylene chloride. The combined organic layers are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to give a white solid. The resulting solid is recrystallized from methylene chloride/hexane to give 5,7-dihydro-5,5,7,7-tetramethyl-3-(m-nitrophenyl)-furo[3,4-e]-as-triazine-4-oxide, m.p. 202°-204°C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[N:13]=[CH:14][N:15](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:16]=1.O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[NH:13][CH2:14][NH:15][CH:16]=1
Reactant: Clc1cccc2c1ccn2Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Clc1cccc2c1ccn2CC1=CNCN1
Temperature: 25 °C
Yield: 20 %

Procedure:
A mixture of powdered KOH (7 mmol) in DMSO (12 mL) at room temperature (rt) under N2 was stirred for 0.5 h. 4-Chloro-1H-indole (Intermediate A1) (1.67 mmol) was added and the mixture was allowed to stir for 2 h at rt. The 4-chloromethyl-1-trityl-1H-imidazole (prepared according to the procedures in: James, L. K. et al; J. Med. Chem. 1997, 20, 721. and Cordi, A. A. et al Eur. J. Med. Chem. 1990, 25, 557, incorporated herein by reference) (Intermediate A2) (1.19 mmol) was added and the mixture was stirred at rt for 18 h. The solution was diluted with H2O and extracted with ethyl acetate. The organic phase was washed with H2O, dried over MgSO4, filtered and evaporated to give the crude product. The residue was purified by chromatography on SiO2 with 1-2% MeOH in CH2Cl2 to give 4-chloro-1-(1-trityl-1H-imidazol-4-ylmethyl)-1H-indole (Intermediate A3). The protected imidazole compound (Intermediate A3) was mixed with H2O (3 mL) and acetic acid (6 mL) and heated to reflux for 1 to 2 h. The mixture was cooled to rt and made basic with 2M NaOH. The aqueous layer was extracted with ethyl acetate (2×15 mL) and the combined organic layers were dried over Na2SO4. This mixture was filtered, freed of solvent and purified by chromatography with 5% NH3:MeOH in CH2Cl2 to give 4-(4-chloro-indol-1-ylmethyl)-1,3-dihydro-imidazole (Intermediate A4) (˜20% over two steps).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:17])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12]/[CH:13]=[CH:14]\[CH2:15]Cl)[C:6]=2[N:7]=1.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CC#N>[NH2:1][C:2]1[NH:3][C:4](=[O:17])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12]/[CH:13]=[CH:14]\[CH2:15][P:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:25])[C:6]=2[N:7]=1
Reactant: CCOP(OCC)OCC
Reactant: Nc1nc2c(sc(=O)n2C/C=C\CCl)c(=O)[nH]1
Solvent: CC#N
Product: CCOP(=O)(C/C=C\Cn1c(=O)sc2c(=O)[nH]c(N)nc21)OCC

Procedure:
A mixture of 5-Amino-3-[(Z)-4-chloro-2-buten-1-yl]thiazolo[4,5-d]pyrimidine-2,7(3H, 6H)-dione (0.75 g, 2.75 mmol), anhydrous CH3CN (75 mL) and triethyl phosphite (10 mL) was stirred and heated at reflux for 6 days while adding additional quantities of triethyl phosphite (2×5 mL) at 2 day intervals. The mixture was evaporated. The residue was triturated with Et2O (2×50 mL) and then dissolved in MEOH (50 mL). Silica gel (25 g) was added and the mixture was evaporated. The dry powder was placed on a silica gel column (5.5×28 cm) and the column was flash eluted with progressively increasing concentrations of MEOH in CH2Cl2 (%MeOH, vol in L): (0, 1), (1, 1), (2, 1), (3, 2), (5, 2), (10, 2). The eluate containing the product was evaporated and the solid residue was dried in vacuum for 16 h. The light yellow solid was stirred with 2-PrOH (20 mL) to obtain a white solid. The solid was collected and dried in vacuum at 80° C. for 16 h: 0.35 g (0.935 mmol, 34%), mp 186-188° C. Ir (KBr): ν3390, 3310 and 3210 (NH, NH2), 1685 (C=O), and 1660 broad (C=O, C=N, C=C) cm-1. Uv λmax (nm) (ε×10-3): pH 1,302 (10.0), 250 (8.92), 220 (31.2); MEOH, 302 (9.60), 250 (8.79), 220 (29.1); pH 11, 292 (7.94), 248 (8.07), 224 (9.88). 1H nmr (DMSO-d6): δ1.23 (t, 6H, 2 CH3), 2.84 (dd, 2H, PCH2), 3.99 (q, 4H, OCH2), 4.40 (br s, 2H, NCH2), 5.55-5.63 (m,2H, 2 CH), 6.93 (br s, 2H, NH2), and 11.14 (br s, 1H, NH). Anal. Calc'd for C13H19N4O5PS (374.35): C, 41.71; H, 5.11; N, 14.97; P, 8.27. Found: C, 41.55; H, 5.02; N, 14.64; P, 8.00.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:23]=1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([Cl:47])[C:33]=1[OH:48]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[CH:23]=2)=[CH:3][C:2]([C:36]2[CH:37]=[C:32]([Cl:31])[C:33]([OH:48])=[C:34]([Cl:47])[CH:35]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: O=C(c1cnc2ccc(Br)cc2c1Nc1cncc(CCN2CCCC2)c1)C1CC1
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cncc(CCN2CCCC2)c1)C1CC1
Yield: 45.7 %

Procedure:
Following general procedure A-1, {6-bromo-4-[5-(2-(pyrrolidin-1-yl)ethyl)pyridin-3-ylamino]quinolin-3-yl}(cyclopropyl)methanone (54 mg, 0.116 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (50 mg, 0.174 mmol) to afford the desired product (29 mg, 46%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.36 (s, 1H), 8.64 (dd, J=16.9, 2.1 Hz, 2H), 8.32 (dd, J=8.8, 2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.99 (t, J=2.0 Hz, 1H), 7.43 (s, 2H), 3.74-3.70 (m, 2H), 3.50-3.43 (m, 2H), 3.24-3.17 (m, 2H), 3.16-3.12 (m, 2H), 2.79-2.76 (m, 1H), 2.19-2.15 (m, 2H), 2.07-2.03 (m, 2H), 1.18-1.07 (m, 4H); ESI MS m/z 547 [C30H28Cl2N4O2+H]+; HPLC>99% (AUC), tR=9.93 min.