Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH2:25].Cl>O1CCCC1>[OH:25][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:2]=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=O)cc2)cc1
Reactant: O
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccccc3O)cc2)cc1
Reaction time: 2 h
Yield: 72 %

Procedure:
In a reaction container equipped with a stirring device, a thermometer and a tap funnel, 14.8 g of potassium tert-buthoxide and 50 ml of tetrahydrofuran are placed. In nitrogen air stream, a solution in which 9.90 g of 2-hydroxy benzyl diethyl phosphonate and 5.44 g of 4-(N,N-bis(4-methylphenyl)amino)benzaldehyde are dissolved in tetrahydrofuran is slowly dropped to the reaction container at room temperature and the reaction is conducted for 2 hours. Next, while cooling down by water, water is added to the resultant and thereafter 2N hydrochloric acid is added to acidify the resultant. Furthermore, tetrahydrofuran is removed by an evaporator and the obtained coarse product is extracted by toluene. The toluene phase is washed with water, sodium hydrogen carbonate aqueous solution and saturated salt solution in this order. After magnesium sulfide is added, the resultant is dehydrated. Subsequent to filtration, toluene is removed and an oily coarse product is obtained. Subsequent to column refinement by silica gel, the resultant is crystallized in hexane and 5.09 g (yield ratio: 72%) of 2-hydroxy-4′-(N,N-bis(4-methylphenyl)amino)stilbene is obtained. The melting point of the product is 136.0 to 138.0° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:9][C:8]([C@@H:10]([NH:13][S@@](C(C)(C)C)=O)[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[ClH:20].O1CCOCC1>CO>[ClH:20].[CH3:1][S:2]([C:5]1[O:9][C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC[C@H](N[S@](=O)C(C)(C)C)c1ccc(S(C)(=O)=O)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@H](N)c1ccc(S(C)(=O)=O)o1
Reaction time: 1 h

Procedure:
To a solution of (R)-2-methyl-propane-2-sulfinic acid[(S)-1-(5-methanesulfonyl-furan-2-yl)-propyl]amide (0.530 g, 1.72 mmol) in methanol (5 mL) was added 4 N HCl in dioxane (2 mL, 8 mmol). After 1 hour, the mixture was concentrated in vacuo to afford (S)-1-(5-methanesulfonyl-furan-2-yl)-propylamine hydrochloride.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:8][C:7]=1[Cl:17])(=[O:3])[CH3:2].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CC#N>[C:1]([O:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([S:13](=[O:15])(=[O:16])[N:14]=[CH:20][N:21]([CH3:23])[CH3:22])=[CH:8][C:7]=1[Cl:17])(=[O:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)OCc1c(F)cc(S(N)(=O)=O)cc1Cl
Solvent: CC#N
Product: CC(=O)OCc1c(F)cc(S(=O)(=O)N=CN(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a solution of 2-chloro-6-fluoro-4-sulfamoylbenzyl acetate (1 g, 3.6 mmol) in CH3CN (20 mL2) at 0° C. under N2 was added 1,1-dimethoxy-N,N-dimethylmethanamine (0.7 ml, 5.4 mmol). The resulting solution was stirred at room temperature 1 h, concentrated under reduced pressure, and purified by column chromatography (DCM/EtOAc=9:1) to afford 2-chloro-4-(N-((dimethylamino)methylene)sulfamoyl)-6-fluorobenzyl acetate (850 mg, 76%) as ivory solid. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.76 (s, 1H), 7.55 (d, 1H), 5.26 (s, 2H), 3.18 (s, 3H), 3.05 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1.[OH-].[Na+]>CO.C1COCC1>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(CN)cn3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(CN)cn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a solution of ethyl 2-(6-(5-(aminomethyl)pyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.18 g, 3.31 mmol) in MeOH/THF (12 mL, 1:1) was added aqueous NaOH solution (250 mg in 3 mL water). After stirring at room temperature for two hours, the reaction mixture was evaporated and then acidified to pH 3 using 1 M HCl. The precipitate was collected and washed with water and dried to give the product as a white solid (0.85 g, yield 78%). No right mass was observed and the structure was confirmed by NMR. 1H NMR (400 MHz, DMSO-d6) δ 12.4 (b, 1H), 9.80 (b, 2H), 9.22 (s, 1H), 8.26 (d, J=2 Hz, 1H), 8.07 (m, 1H), 7.21 (d, J=2 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.01 (m, 1H), 5.51 (dd, J=9.2, 4 Hz, 1H), 4.15 (s, 2H), 3.07 (dd, J=15.6, 2.4 Hz, 1H), 2.28 (s, 3H), 2.12 (dd, J=15.2, 9.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]([C:24]1[CH:36]=[CH:35][C:27]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:26][C:25]=1[O:37][CH3:38])=[C:22]=S>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:22]([NH:21][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:26][C:25]=3[O:37][CH3:38])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(CN2CCOCC2)ccc1N=C=S
Product: COc1cc(CN2CCOCC2)ccc1Nc1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 11 %

Procedure:
In a similar fashion as for the synthesis of Compound LXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide was reacted with 4-(4-isothiocyanato-3-methoxybenzyl)-morpholine to afford the title compound as a tan solid (11%). 1H NMR (d-6 DMSO): 10.0 (br m, 1H), 8.78 (m, 1H), 8.62 (m, 1H), 7.86 (m, 2H), 7.36 (m, 1H), 7.25 (m, 1H), 7.10 (m, 1H), 6.43 (m, 2H), 5.08 (m, 1H), 4.34 (m, 2H), 3.98 (s, 3H), 3.29 (m, 4H), 3.12 (m, 4H), 2.92 (s, 1H), 2.86 (s, 1H), 2.62 (m, 1H), 2.21 (m, 1H), 1.69 (m, 1H), 1.44 (m, 1H). MS: 524.02 (M+H). HPLC retention time: 1.74 minutes (G Method).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17]C(=O)OC(C)(C)C)[CH2:12]1)(=[O:10])=[O:9].[ClH:25].CCOCC>C(Cl)Cl>[ClH:25].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH2:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CCCN(S(=O)(=O)c2ccccc2Br)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: NC1CCCN(S(=O)(=O)c2ccccc2Br)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of racemic tert-butyl (1-((2-bromophenyl)sulfonyl)piperidin-3-yl)carbamate (82 mg, 0.20 mmol) in CH2Cl2 (5 mL) was treated with 2 N HCl/Et2O (1 mL, 2 mmol) and stirred 16 hours at rt. The reaction mixture was then concentrated to dryness to give the title compound in quantitative yield. The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][S:31][CH2:32][CH2:33][OH:34])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.ClC1C=CC=C(C(OO)=[O:43])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][S:31]([CH2:32][CH2:33][OH:34])=[O:43])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OCCSCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=S(CCO)CCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of 2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol (100 mg) in dichloromethane (10 mL) was added dropwise a 70% solution of 3-chloroperbenzoic acid (58 mg) in dichloromethane (5.0 mL) at −78° C. The mixture was stirred at −78° C. for 1 hr, and aqueous sodium thiosulfate solution was added. After stirring at room temperature for 0.5 hr, the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=4:1) to give the title compound (87 mg) as colorless crystals.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][C:25]=4[Cl:33])[C:20]([CH3:22])=[N:21][C:16]3=[CH:15][CH:14]=2)=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>C(O)C>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:19]2[C:17]3=[N:18][C:13]([C:11](=[O:12])[NH:10][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:8])=[O:9])=[CH:14][CH:15]=[C:16]3[N:21]=[C:20]2[CH3:22])=[C:25]([Cl:33])[CH:26]=1
Reactant: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc([N+](=O)[O-])cc1Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(N)cc1Cl
Yield: 32.6 %

Procedure:
5-(Benzenesulfonylcarbamoyl)-3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (245 mg) was suspended in ethanol (3 ml) and reduced iron (141 mg) and acetic acid (0.289 ml) were added, and the mixture was refluxed under heating overnight. The reaction mixture was filtered through Celite, and the filtrate was washed with a mixed solvent of methanol/chloroform (1/4) and the filtrate was concentrated under reduced pressure. To the concentrated residue were added a saturated aqueous sodium hydrogen carbonate solution, water and a mixed solvent of methanol/chloroform (1/4) and the aqueous phase was made alkaline. The precipitated insoluble matter was filtered through Celite and the filtrate was washed with a mixed solvent of methanol/chloroform (1/9). The filtrate was partitioned and the organic layer was dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure to give a crude product as a pale-brown powder. The crude product (100 mg) was recrystallized from N,N-dimethylformamide-water to give 3-(4-amino-2-chlorobenzyl)-5-(benzenesulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine (75 mg) as brown crystals.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].S(=O)(=O)(O)O>O>[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:9]2[CH:10]=[CH:11][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:18][CH:17]=1)(=[O:22])[CH3:21]
Reactant: Oc1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 85.7 %

Procedure:
A mixture of 4-(1-phenyl-1H-pyrazol-3-yl)aminophenol (2.0 g), acetic anhydride (4 g) and sulphuric acid (0.2 g) was heated at 100° C. on the steam bath for 15 minutes, water was added and the product was collected by filtration and dried to give the sub-title compound (2.0 g) as a brown solid.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:17]([OH:19])=[O:18])[CH:12]=[CH:13][C:14]=3[O:15][CH3:16])[CH:10]=2)=[O:5])[CH2:3][CH2:2]1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].Cl.CN(C)CCCN=C=NCC.O>ClCCl.CN(C)C1C=CN=CC=1>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:18][C:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:8]3[O:7][C:6]([C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])=[CH:10][C:9]=23)=[O:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: COc1ccc(C(=O)O)c2cc(C(=O)C3CC3)oc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(=O)C3CC3)oc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a stirred suspension of 2-cyclopropanecarbonyl-7-methoxybenzofuran-4-carboxylic acid (0.50 g) in dichloromethane (30 ml) under an atmosphere of nitrogen was added 4-nitrophenol (0.29 g), 4-dimethylaminopyridine (20 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.41 g). The reaction mixture was stirred at room temperature for 18 h. Water (30 ml) was added and the mixture extracted with dichloromethane (150 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 40% ethyl acetate in hexane afforded the title compound as a pale yellow solid (0.59 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19])[CH2:6]2)=[O:4].C(N(CC)CC)C.[CH2:38]([N:42]([CH2:45][CH2:46][CH2:47][CH3:48])[S:43]Cl)[CH2:39][CH2:40][CH3:41]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([N:20]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[S:43][N:42]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:19])[CH2:6]2)=[O:4]
Reactant: CCCCN(CCCC)SCl
Reactant: COC(=O)C12CCc3ccccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)SN(C(=O)N1CC2(C(=O)OC)CCc3ccccc3C2=N1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Step B (Example 1) (0.4 g, 0.96 mmol) in 8 ml methylene chloride cooled to 0° C. was added triethylamine (0.15 g) and dibutylaminosulfenylchloride (0.2 g). The reaction mixture was warmed to room temperature and stirred for one hour. The mixture was subjected to silica gel column chromatography using hexane-ether (6:1) as the eluent. The title compound was obtained (0.24 g)in high purity.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH3:11][Mg]Br>C(OCC)(=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([OH:5])[CH3:11]
Reactant: Nc1cccc(Cl)c1C=O
Reactant: C[Mg]Br
Solvent: CCOC(C)=O
Product: CC(O)c1c(N)cccc1Cl

Procedure:
This compound was prepared using General Method 1 (EXAMPLE 1) from 2-amino-6-chlorobenzaldehyde (45 mg, 0.29 mmol) and methylmagnesium bromide (3 M in ether, 0.24 mL) to afford (±)-(2-amino-6-chlorophenyl)ethanol after flash chromatography (4:1 hexanes:ethyl acetate).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:55]=[CH:54][C:12]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:50]=[C:49]([CH3:51])[C:39]([NH:40][C:41](=[O:48])[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[N:38][C:36]3=[O:37])[C@H:32]([OH:52])[C@@H:31]2[OH:53])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[Si:56](Cl)([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57]>C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[CH3:7][O:8][C:9]1[CH:55]=[CH:54][C:12]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:50]=[C:49]([CH3:51])[C:39]([NH:40][C:41](=[O:48])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)=[N:38][C:36]3=[O:37])[C@H:32]([O:52][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[C@@H:31]2[OH:53])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(NC(=O)c4ccccc4)nc3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(NC(=O)c4ccccc4)nc3=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.7 %

Procedure:
Anhydrous pyridine (3.6 mL) was added to a solution of 5′-O-(4,4′-dimethoxitrityl)-N-benzoyl-5-methylcytidine (7.06 g, 10.64 mmol) and AgNO3 (2.17 g, 12.75 mmol) in dry THF (71 mL) and stirred at room temperature for 20 min under an argon atmosphere. Followed by addition of tert-butyldimethylsilyl chloride (1.89 g, 12.81 mmol) in dry THF (6 mL) and stirred at the same temperature for 2-3 h. The solids were filtered off and the filtrate was concentrated to a crude residue which was applied to a column of silica gel eluted with hexane-ethyl acetate (3:1) to give a pure title compound (3.04 g, 37%), and a mixture of 2′- and 3′-isomers (3.04 g) as amorphous solid. 1H-NMR (DMSO-d6, 400 MHz): δ 12.96 (br, 1H), 8.20-7.81 (m, 2H, ArH), 7.82 (s, 1H), 7.58-7.22 (m, 12H, ArH), 6.92-6.90 (m, 4H, ArH), 5.80 (d, 1H, J=3.6 Hz, H-1′), 5.20 (d, 1H, J=6.4 Hz, 3′-OH), 4.32 (dd, 1H, H-2′), 4.16-4.13 (dd, 1H, H-3′), 4.08 (m, 1H, H-4′), 3.78 (s, 6H, 2OCH3), 3.38-3.25 (m, 2H, H-5′), 1.80 (s, 3H, 5-CH3), 0.86 (s, 9H, t-Bu), 0.08 (s, 6H, 2 CH3).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][N:5]1[CH2:9][C:8]([OH:10])=[C:7]([C:11]2[CH2:15][N:14]([CH2:16][C:17]([O:19]C)=[O:18])[C:13](=[O:21])[CH:12]=2)[C:6]1=[O:22].[OH-].[Na+].Cl>O>[OH:10][C:8]1[CH2:9][N:5]([CH2:4][C:3]([OH:23])=[O:2])[C:6](=[O:22])[C:7]=1[C:11]1[CH2:15][N:14]([CH2:16][C:17]([OH:19])=[O:18])[C:13](=[O:21])[CH:12]=1
Reactant: COC(=O)CN1CC(C2=C(O)CN(CC(=O)OC)C2=O)=CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CC(C2=C(O)CN(CC(=O)O)C2=O)=CC1=O
Reaction time: 2 h

Procedure:
6.5 g (0.02 mol) of 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid dimethyl ester are stirred in 100 ml of water and 20 ml of concentrated aqueous sodium hydroxide solution for 12 hours at 90°. The solution is then rendered strongly acidic with concentrated aqueous hydrochloric acid solution while cooling with an ice-water bath. The resulting suspension is stirred for a further 2 hours in order to complete the reaction, then filtered, washed with water and acetone and dried under a high vacuum. 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid is obtained in the form of white microcrystals having a melting point of 268° (decomposition).
Reaction SMILES: Cl[C:2]1(O)[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=1[O:34][CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=4)=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:29][C:28]=1[O:34][CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(N)cc1OCCO[Si](C)(C)C(C)(C)C
Reactant: OC1(Cl)NC=Nc2cc(-c3ncccc3C(F)(F)F)ccc21
Solvent: CC#N
Product: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1OCCO[Si](C)(C)C(C)(C)C

Procedure:
Stir 4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol (1.85 g, 6 mmol) and 4-tert-butyl-3-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenylamine (1.94 g, 6 mmol) in acetonitrile (100 mL) at 80° C. for 4 hours. Cool the mixture and collect the precipitate. Partition the residue between ethyl acetate and sodium bicarbonate solution and extract with further ethyl acetate. Dry the combined extracts (MgSO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][S:36]([CH3:35])(=[O:38])=[O:37])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1
Yield: 11.3 %

Procedure:
To a solution of compound 8a (200 mg, 0.450 mmol) in pyridine (4 mL) was added methanesulfonyl chloride (150 mg, 1.32 mmol). The resulting solution was stirred in a 10 mL sealed tube at 30° C. for 8 h. The reaction was quenched with H2O (10 mL). The resulting solids were collected by filtration. The crude material was purified by flash column chromatography on silica gel, eluting with DCM/MeOH (100:1 v/v) to obtain compound 8b as a light yellow solid (26.8 mg, 11% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 10.91 (s, 1H), 8.55 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.23 (s, 1H), 8.12 (d, J=2.4 Hz, 1H), 8.10-7.93 (m, 2H), 7.87 (d, J=4.8 Hz, 1H), 7.83 (d, J=2.7 Hz, 1H), 7.78-7.73 (m, 1H), 7.68-7.54 (m, 2H), 7.44 (s, 1H), 7.17 (d, J=8.7 Hz, 1H), 4.40-4.20 (m, 4H), 3.85-3.75 (m, 4H), 3.39 (s, 3H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H25N7O3S: 528.2 (M+H). Found 528.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:24])[C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:24])[C@@H:18]([OH:23])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CC(=O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
To a stirred solution of 2(S)-t-Butyloxycarbonylamino-1-cyclohexyl-3(R)-hydroxy-6-methylheptan4-one (200 mg, 0.586 mmol) in THF (10 mL) was added NaBH4 (22 mg, 0.586 mmol). After 2 hours, the solvent was evaporated and the residue was partitioned between ethyl acetate and brine. The organic phase was washed (brine), dried (MgSO4), filtered and evaporated. The residue was recrystallized from methylcyclohexane to give 76 mg (38%) of the desired product. M.p. 130°-131° C. The mother liquor was chromatographed (silica gel, ether/hexane) to afford 43 mg (21%) more.