Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:15]1[N:16]=[CH:17][N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:19]=1)([OH:14])[CH3:13].[OH-].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)([OH:14])[CH3:13]
Reactant: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc(C(F)(F)F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(O)(c1c[nH]cn1)c1cccc(C(F)(F)F)c1F
Yield: 85.4 %

Procedure:
1-(2-fluoro-3-trifluoromethyl-phenyl)-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate B2) (4.7 mmol) in acetic acid (13 mL) and water (3 mL) was heated to 100° C. for 1 h. The mixture was cooled to rt and basified with 2M NaOH. The compound was extracted with ethyl acetate and the solution was concentrated onto silica gel. The product was eluted with 3-5% NH3-MeOH: CH2Cl2 to give 1-(2-fluoro-3-trifluoromethyl-phenyl)-1-(1H-imidazol-4-yl)-ethanol (Intermediate B3) 1.1 g (85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]([NH2:50])[C:14]3[N:15]=[CH:16][N:17]([C:48]=3[N:49]=2)[C@@H:18]2[O:47][C@H:37]([CH2:38][O:39][Si](C(C)(C)C)(C)C)[C@@H:28]([O:29][Si](C(C)(C)C)(C)C)[C@H:19]2[O:20][Si](C(C)(C)C)(C)C)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]([NH2:50])[C:14]3[N:15]=[CH:16][N:17]([C:48]=3[N:49]=2)[C@@H:18]2[O:47][C@H:37]([CH2:38][OH:39])[C@@H:28]([OH:29])[C@H:19]2[OH:20])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(OCCc2ccc(Cl)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 46.4 %

Procedure:
To a solution of 2-[2-(4-chlorophenyl)ethoxy]-2′,3′,5′-tri-O-(TERT-butyldimethylsilyl)-adenosine (Example 1, 500 mg, 0.654 mmol) in 7 mL of anhydrous methanol flushed with nitrogen was added 3.27 mL of a 1.0 M solution of TBAF in THF (5 equiv). The reaction was heated to 50° C. for 48 hours. Upon disappearance of the starting material as indicated by LC/MS analysis, the reaction mixture was allowed to cool to room temperature and was concentrated to dryness. Ethyl acetate (20 ml) and water (20 ml) were added and stirred for 5 minutes. The layers were separated and the aqueous layer reextracted with ethyl acetate (2×20 ml). The organic phases were combined, dried over MgSO4 and concentrated to give an oil. The crude material was then purified on silica gel, eluting with a gradient of 0%-10% methanol in CH2Cl2, affording 128 mg (46%) of the desired product as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])C.[OH-].[Na+]>CO.O>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH:6]=[CH:5][C:4]([OH:22])=[O:3])=[C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:9]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C=Cc1ccc(C(C)(C)C)cc1OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCOc1cc(C(C)(C)C)ccc1C=CC(=O)O
Yield: 99.3 %

Procedure:
3-[4-tert-Butyl-2-(2-methoxyethoxy)phenyl]acrylic acid ethyl ester (40.4 mg, 0.132 mmol, 1 eq) and sodium hydroxide (52.8 mg, 1.32 mmole, 10 eq) were added in methanol and H2O. The reaction mixture was purified according to step 2 of Example 22 to give 3-[4-tert-Butyl-2-(2-methoxyethoxy)phenyl]acrylic acid (36.5 mg, 77.3%). 3-[4-tert-Butyl-2-(2-methoxyethoxy)-phenyl]acrylic acid (26.4 mg, 0.095 mmol, 1 eq.), Diethylcyanophosphine (17.3 μl, 0.114 mmol, 1.2 eq), N-(4-Aminomethyl-2-fluoro-6-vinylphenyl)methanesulfonamide (40.8 mg, 0.1114 mol, 1.2 eq.), and Triethylamine (39.7 μl, 0.285 mmol, 3 eq) were added in DMF. The mixture was stirred for overnight at room temperature. The reaction mixture was purified according to Example 17 to give a whitish solid (28.4 mg, 59.2%).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:18][C:19]2[S:20][CH:21]=[C:22]([CH2:24][OH:25])[N:23]=2)=[O:17])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.CS(C)=O.N1C=CC=CC=1.S(=O)(=O)=O>C(Cl)Cl.O>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:18][C:19]2[S:20][CH:21]=[C:22]([CH:24]=[O:25])[N:23]=2)=[O:17])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CO)cs2)c(C(=O)C2CCCC2)c1
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)Nc2nc(C=O)cs2)c(C(=O)C2CCCC2)c1
Reaction time: 1 h
Yield: 89 %

Procedure:
To 1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-[4-hydroxymethyl-thiazol-2-yl]-urea (1.8 g, 5 mmol) in CH2Cl2 (40 mL) at 0° C. was added Et3N (2.88 mL, 20 mmol), dimethyl sulfoxide (10 mL) followed by sulfur trioxide-pyridine (2.38 g, 15.0 mmol). The reaction mixture was stirred for 1 h and then poured into water (30 mL). The mixture was extracted with CH2Cl2 and the organic layers was washed with 1.0 N ammonium chloride (2×20 mL), water (2×20 mL), brine (1×20 mL), dried (Na2SO4) and concentrated to give a solid. The solid was purified by column chromatography (silica, Hexanes/EtOAc, 20-50%) to obtain 1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-(4-formyl-thiazol-2-yl)-urea (1.59 g, 86%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.[ClH:13].Cl.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:24][CH:25]=[CH:26][N:27]=2)=[CH:18][CH:17]=1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[ClH:13].[ClH:13].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([N:28]3[CH2:29][CH2:30][N:31]([CH2:7][C:5]4[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3][N:2]([CH3:1])[CH:6]=4)[CH2:32][CH2:33]3)=[N:24][CH:25]=[CH:26][N:27]=2)=[CH:18][CH:17]=1
Reactant: Cn1cc(C=O)c(C(F)(F)F)n1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(CN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)c(C(F)(F)F)n1
Reaction time: 0.25 h
Yield: 149.2 %

Procedure:
Combine 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde (0.17 g, 0.97 mmol) and 3′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.35 g, 1.06 mmol) in DCM (20 mL) and treat with triethylamine (0.30 mL, 2.12 mmol). After stirring for 15 min, add glacial acetic acid (0.08 mL, 1.46 mmol) then sodium triacetoxyborohydride (0.31 g, 1.46 mmol). Stir at room temperature for 18 hr. Concentrate and purify using SCX chromatography and further purify using silica gel chromatography (5% 7 M ammonia in methanol/DCM). Dissolve the free base in methanol (5 mL) and treat with ammonium chloride (0.107 g). Concentrate the resulting solution to give the title compound (0.39 g, 81%). MS: m/z=421.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1.[CH:17]1([C:20]2[N:42]=[C:23]3[N:24]=[C:25]([C:34]4[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=4)[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:27][N:22]3[N:21]=2)[CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[CH:17]1([C:20]2[N:42]=[C:23]3[N:24]=[C:25]([C:34]4[CH:41]=[CH:40][C:37]([CH2:38][N:1]5[CH2:2][CH2:3][CH:4]([C:7]6[CH:16]=[N:15][C:14]7[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=7)[N:8]=6)[CH2:5][CH2:6]5)=[CH:36][CH:35]=4)[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:27][N:22]3[N:21]=2)[CH2:18][CH2:19]1
Reactant: c1ccc2nc(C3CCNCC3)cnc2c1
Reactant: O=Cc1ccc(-c2nc3nc(C4CC4)nn3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: c1ccc(-c2cn3nc(C4CC4)nc3nc2-c2ccc(CN3CCC(c4cnc5ccccc5n4)CC3)cc2)cc1
Reaction time: 1 h
Yield: 49.7 %

Procedure:
125.3 mg (0.59 mmol) 2-Piperidine-4-ylquinoxaline are dissolved in 5.2 mL NMP. After addition of 0.2 mL triethylamine the reaction mixture is stirred for one hour. 200 mg (0.59 mmol) 4-(2-cyclopropyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (intermediate example 4.0) and 0.06 mL acetic acid are added. The reaction mixture is stirred overnight at room temperature. 137 mg (0.65 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for four hours. Saturated NaHCO3 is added to the reaction mixture, the precipitate is filtered off and purified by chromatography on silica gel (dichloromethane/methanol). 157.8 mg (47.5%) of the pure product are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[N+:21]([C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(I)c2c(Oc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Temperature: 60 °C

Procedure:
To a reaction vial was added 2,4-dichloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (3.50 g, 7.9 mmol), as prepared in Example 5, step 1, 3-nitrophenol (1.1 g, 7.9 mmol), DMF (26 mL) and K2CO3 (2.18 g, 16 mmol, 2 mol eq). The reaction mixture was stirred and heated to 60° C. (block temperature) for 1 hr. The volatiles were removed and water (30 mL) was added. Ethyl acetate (120 mL) was added and the organic layer was separated, washed with water (20 mL), brine (20 mL), dried over Na2SO4 and evaporated to give crude product (TLC: Rf 0.6 (major) and 0.4 (minor) in 20% ethyl acetate-80% heptane). The product was purified on silica to give a light yellow oil, which solidified to a light yellow solid (3.65 g, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28-8.31 (m, 1H) 8.26 (d, J=8.06 Hz, 1H) 8.02 (s, 1H) 7.90-7.94 (m, 1H) 7.83-7.89 (m, 1H) 5.60 (s, 2H) 3.53-3.67 (m, 2H) 0.84-0.99 (m, 2H) 0.00 (s, 9H). m/z (APCI+) for C18H20ClIN4O4Si 547.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.CN(C)C=O.[CH3:32][CH:33]([CH3:37])[C:34](Cl)=[O:35].C(N(CC)CC)C>O>[CH3:32][CH:33]([CH3:37])[C:34]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1)=[O:35]
Reactant: CC(C)C(=O)Cl
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Yield: 26 %

Procedure:
A mixture comprising 50 mg (130 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20), 5 mL N,N-dimethylformamide, 13.7 μL 2-methylpropanoyl chloride and 18.2 mL N,N-diethylethanamine was stirred at 23° C. overnight. Water was added and the solvents were removed. The residue was purified by chromatography to give 16 mg (26%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH:39]1([CH2:42]Br)[CH2:41][CH2:40]1>CC(CC(C)C)=O>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][N:11]([CH2:42][CH:39]2[CH2:41][CH2:40]2)[C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: c1ccc(COC[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)CN2CC2CC2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.25 g, 0.62 mmol) was dissolved in methyl-isobutylketone (15 ml). Potassium carbonate (0.17 g, 1.2 mmol) and potassium iodide (0.03 g, 0.18 mol) was added. After stirring for 10 min at 25° C. cyclopropylmethylbromide (0.078 ml, 0.81 mmol) was added. The mixture was stirred under a N2 atmosphere at 80° C. for 24 hours and evaporated in vacuo. Water (20 ml) was added and extraction with methylene chloride (3×20 ml), drying of the organic phases with magnesium sulphate and evaporation of the solvent in vacuo afforded a yellow oil. Purification of the crude product twice on a silica gel column (1: Eluent: CH2Cl2/MeOH (19:1) and 2: Eluent: CH2Cl2/MeOH (39:1)) gave (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-cyclopropylmethylpyrrolidine (0.213 g, yield: 75%) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH2:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([B:24]2[O:29]CC(C)(C)C[O:25]2)=[CH:20][CH:19]=1.CC1C=CC(B(O)O)=CC=1.CC(C)(CO)CO.BrN1C(=O)CCC1=O.[ClH:57]>CN1C(=O)CCC1.C1CCCCC1.C(OCC)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N.O>[ClH:57].[CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([B:24]([OH:29])[OH:25])=[CH:20][CH:19]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CC1(C)COB(c2ccc(CBr)cc2)OC1
Reactant: CCC1=Nc2ccccc2C(=O)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)(CO)CO
Agent: Cc1ccc(B(O)O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc(OCc2ccc(B(O)O)cc2)c2ccccc2n1
Reaction time: 18 h

Procedure:
A solution of 2-ethyl-4-quinolone (6.9 g; 0.04 mole) in (NMP) (50 ml) was added over 30 minutes to a stirred suspension of sodium hydride (1.6 g of a 60% dispersion in mineral oil; 0.04 mole) in NMP (50 ml) and the mixture stirred for 30 minutes. A solution of 2-(4-bromomethylphenyl)-5,5-dimethyl-1,3,2-dioxaborinane in cyclohexane [previously prepared by heating a mixture of 4-methylphenylboronic acid (6.8 g) and 2,2-dimethylpropan-1,3-diol (5.2 g) in cyclohexane (150 ml) at reflux with azeotropic removal of water, followed by the addition of N-bromosuccinimide (8.9 g) and azo(bisisobutyronitrile) (0.2 g), heating the mixture at reflux for 3 hours, and removing suspended succinimide by filtration] was added and the mixture was heated at 60°-70°]C. for 18 hours. The mixture was allowed to cool and acetic acid was then added until the mixture was at pH 4, followed by water (200 ml) and ethyl acetate (200 ml). The mixture was stirred for 20 minutes and then the organic phase was separated, washed with water and dried (MgSO4). Volatile material was removed by evaporation to give a crystalline solid. The solid was dissolved in ethyl acetate (150 ml), concentrated hydrochloric acid (3 ml) and water (3 ml) were added and the mixture was stirred for 18 hours. The resultant precipitate was collected by filtration, washed with ethyl acetate and dried to give 4-[(2-ethylquinolin-4-yloxy)methyl]phenylboronic acid hydrochloride (7 g) as a solid; NMR similar to that of compound G of Procedure B, step (ii).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.Cl.[NH:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])N>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[C:23]4[C:15](=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=[CH:21][CH:22]=4)[NH:13][C:7]=3[C:6]=2[CH:11]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: O=C1COc2ccc(Br)cc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c1[nH]c1c3cc(Br)ccc3oc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of 5-bromo-3(2H)-benzofuranone (3.10 g, 14.6 mmol) [Ellingboe, J. et al., J. Med. Chem. 1992, 35 (7), 1176-1183] in ethanol (100 mL) was added a solution of 2-hydrazinobenzoic acid hydrochloride (5.49 g, 29.1 mmol) in deionized water (200 mL). The mixture was stirred for one hour at room temperature and then allowed to sit while cooled (0° C.). Vacuum filtration and drying in vacuo afforded 3.65 g (72%) of the title compound as a brown solid: mp 195° C. (dec) which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([C:8]([O:10][C@@H:11]2[C@H:16]([CH3:17])[O:15][C@@H:14]([CH2:18]/[CH:19]=[CH:20]/[CH:21]=[CH2:22])[CH2:13][C@@H:12]2[NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:32]1(=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[CH:34]=[CH:33]1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C@@H:11]2[C@H:16]([CH3:17])[O:15][C@@H:14]([CH2:18][CH:19]3[CH:33]4[CH:34]([C:35](=[O:42])[C:36]5[C:41]([C:32]4=[O:43])=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH2:22][CH:21]=[CH:20]3)[CH2:13][C@@H:12]2[NH:23][C:24](=[O:29])[C:25]([F:28])([F:26])[F:27])=[O:9])=[CH:30][CH:31]=1)([O-:3])=[O:2]
Reactant: C=C/C=C/C[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@H](C)O1
Reactant: O=C1C=CC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: C[C@@H]1O[C@@H](CC2C=CCC3C(=O)c4ccccc4C(=O)C23)C[C@H](NC(=O)C(F)(F)F)[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 65.4 %

Procedure:
Ninety mg (0.203 mmoles) of (E)-1-(2,3,6-trideoxy-4-O-p-nitrobenzoyl-3-trifluoroacetamido-α-L-lyxo-hexopyranosyl)-2,4-pentadiene and 22.0 mg (0.140 mmoles) of 1,4 naphthoquinone were mixed in 10 ml toluene and the mixture was heated under N2 at 80°-88° C. for 4 hr. The reaction was chilled to 0° C. and filtered to give 55 mg (65%) 1,4,4a,9a-tetrahydro-1-[(2,3,6-trideoxy-4-O-p-nitrobenzoyl-3-trifluoroacetamido-α-L-lyxo-hexo-pyranosyl)methyl]-anthracene-9,10-dione in impure form.
Reaction SMILES: C(OC([NH:8][C:9]1[C:13]([NH:14]C(OC(C)(C)C)=O)=[CH:12][S:11][C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][CH:30]=[C:31]([NH:41]C(OC(C)(C)C)=O)[C:32]=2[NH:33]C(=O)OC(C)(C)C)=[CH:24][CH:23]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:33][C:32]1[C:31]([NH2:41])=[CH:30][S:29][C:28]=1[C:25]1[CH:24]=[CH:23][C:22]([C:10]2[S:11][CH:12]=[C:13]([NH2:14])[C:9]=2[NH2:8])=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1csc(-c2ccc(-c3scc(NC(=O)OC(C)(C)C)c3NC(=O)OC(C)(C)C)cc2)c1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1csc(-c2ccc(-c3scc(N)c3N)cc2)c1N
Reaction time: 3 h

Procedure:
To the resulting tert-butyl 2-[4-(3,4-bis(tert-butoxycarbonylamino)thien-2-yl)phenyl]-4-tert-butoxycarbonylaminothien-3-ylcarbamate was added 80 equivalents of trifluoroacetic acid, and a reaction was performed at 25° C. for 3 hours. The resulting reaction liquid was dropped slowly to a saturated aqueous sodium carbonate solution to neutralize, thereby stopping the reaction. Ethyl acetate was added to the reaction liquid and stirred, and then the organic layer was taken and the solvent was distilled off, and the residue was purified by silica gel column chromatography using an ethyl acetate/hexane solvent, so that 2-[4-(3,4-diaminothien-2-yl)phenyl]thiophene-3,4-diamine was obtained. The yield based on the charged tert-butyl 2-[4-(3,4-bis(tert-butoxycarbonylamino)thien-2-yl)phenyl]-4-tert-butoxycarbonylaminothien-3-ylcarbamate was 90%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[H-].[Na+].[CH2:10](Br)[C:11]#[CH:12].O>O1CCCC1>[CH:10]([N:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1)=[C:11]=[CH2:12]
Reactant: O=Cc1cc[nH]c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C=Cn1ccc(C=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1 g of pyrrole-3-carboxaldehyde was dissolved in 25 ml of tetrahydrofuran with stirring at the ambient temperature for 15 minutes and after cooling to 0° to 5° C., 528 mg of sodium hydride as 50% in oil were added with stirring for 10 minutes cold. The temperature was allowed to return to the ambient with stirring for 40 minutes under nitrogen and 1 ml of propargyl bromide was added with stirring for a further 2 hours at 40° to 50° C. Then, the reaction mixture was poured into 15 ml of water, and was extracted with methylene chloride. The extracts were dried and concentrated by distilling off the solvent. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (7-3) to obtain 1.166 g of 1-propadienyl-1H-pyrrole-3-carboxaldehyde.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:35]([O:36][CH3:37])=[CH:34][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:35]([O:36][CH3:37])=[CH:34][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc2c(cc1N)CCN(CC(C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CC(C)O)CC2
Yield: 53 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol. Product was isolated as a tan foam (55 mg, 53%). mp: 120° C., MS (ESI+): 513 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.66 (s, 1H), 6.57 (s, 1H), 6.51 (s, 1H), 6.33 (s, 2H), 5.60 (s, 1H), 5.35 (s, 1H), 5.32 (s, 1H), 4.47 (t, J=8 Hz, 1H), 3.88 (s, 4H), 3.09 (s, 1H), 2.89-2.87 (m, 7H), 2.63 (m, 2H), 2.53 (d, 2H), 2.28 (d, J=10 Hz, 2H), 1.67 (d, J=8 Hz, 1H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]3[N:22]([CH2:23][C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])[C:21]([CH3:32])=[C:20]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:19](=[O:40])[N:18]3[C:41]=2[CH2:42][N:43]([CH3:51])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:11][CH:10]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[CH2:23][N:22]1[C:21]([CH3:32])=[C:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:19](=[O:40])[N:18]2[C:41]([CH2:42][N:43]([CH3:51])[CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][CH:11]=3)[N:16]=[C:17]12
Reactant: Cc1c(Cc2ccccc2)c(=O)n2c(CN(C)Cc3ccccc3)c(-c3ccc(NC(=O)OC(C)(C)C)cc3)nc2n1Cc1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)c(=O)n2c(CN(C)Cc3ccccc3)c(-c3ccc(N)cc3)nc2n1Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the compound obtained in Example 19 (0.53 g, 0.77 mol) in dichloromethane (20 ml) is added trifluoroacetic acid (0.24 ml, 3.07 mmol) with ice-cooling. An additional amount of trifluoroacetic acid (1.5 ml) is added at room temperature and is stirred for 5 hours at room temperature. The reaction mixture is partitioned between chloroform (100 ml) and aqueous saturated NaHCO3 solution (30 ml). The aqueous layer is extracted with chloroform (30 ml). The combined organic solution is washed with saturated saline (20 ml), dried over Na2SO4, successively evaporated under reduced pressure to give the residue, which is chromatographed on silica gel to afford a pale brown colorless amorphous (0.41 g, 90%).