Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([OH:13])=[CH:4][CH:3]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:13][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(I)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(I)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 4.2 %

Procedure:
Ethyl 5-iodosalicylate (457 mg), 4-chloro-6,7-dimethoxyquinoline (348 mg), and 4-dimethylaminopyridine (573 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (31 mg, yield 4%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C.Cl>C1COCC1.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:33])=[O:34])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=[O:12]
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1
Reactant: O=C(O)c1cc2ccccc2o1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
Benzofuran-2-carboxylic acid (310 mg, 1.9 mmol) was mixed with 3 ml of oxalyl chloride and refluxed for 1 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed by vacuum. The residue was dissolved in 4 ml of dichloromethane and was added to a mixture of 400 mg (1.6 mmol) of 4′-amino-biphenyl-4-sulfonic acid, N,N-diisopropylethylamine (0.92 ml, 4 eq) and 4 ml of THF in an ice/water bath. The mixture was stirred at room temperature for 4 h. The reaction mixture was mixed with 2N HCl and in the process a suspension formed. The solid was collected by centrifugation and was washed with chloroform and 2N HCl to provide 540 mg of 4′-[(benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonic acid, obtained as pale brown solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:24][CH3:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1)[CH3:2].[OH:36][CH2:37][C:38](O)=[O:39].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>C1COCC1.C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:24][CH3:25])[CH2:23][CH2:22][N:21]([C:37](=[O:36])[CH2:38][OH:39])[CH2:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=C(O)CO
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCNCC3)n(C)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCN(C(=O)CO)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(4-methoxypiperidin-4-yl)-9-methyl-6-morpholin-4-yl-9H-purine (150 mg, 0.32 mmol), hydroxyacetic acid (36 mg, 0.47 mmol), HOBt (47 mg, 0.35 mmol), NMM (77 μL, 0.69 mmol) and EDCI (91 mg, 0.47 mmol) in THF (3 mL) was allowed to stir at r.t. for 4 h. The resulting mixture was diluted with DCM and washed with sat. aq. NaHCO3, dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, THF:EtOAc, 0-50%) then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 823 (88 mg, 52%). LCMS (method I): RT 3.25 min, [M+H]+ 535.3. 1H NMR (DMSO, 400 MHz): δ 8.05-8.04 (1 H, m), 7.64-7.63 (1 H, m), 7.26-7.25 (2 H, m), 4.54 (1 H, t, J=5.40 Hz), 4.17-4.06 (6 H, m), 3.92 (3 H, s), 3.78 (4 H, t, J=4.51 Hz), 3.65-3.55 (1 H, m), 3.40-3.25 (3 H, m), 3.18 (1 H, m), 3.09 (3 H, s), 2.17-2.14 (4 H, m), 1.35 (3 H, t, J=7.43 Hz)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.CO>CCOCC>[O:19]=[C:13]([NH:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)O1
Solvent: CO
Solvent: CCOCC
Product: O=C(O)CCC(=O)NCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.2 %

Procedure:
A solution of 15.0 g (85.6 mmol) of (3-(trifluoromethyl)phenyl)methylamine in ether (40 ml) was added dropwise to a suspension of 7.5 g (85.6 mmol) of succinic anhydride in ether (450 ml) within 30 min. The mixture was then stirred for 72 h at room temperature. The deposit obtained was filtered and dried. After column chromatography (EE/MeOH 1:1) of the residue, 10.4 g (37.8 mmol, 44%) of 4-oxo-4-(3-(trifluoromethyl)benzylamino)butyric acid were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[NH3:15]>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([NH2:15])=[O:8]
Reactant: N
Reactant: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Solvent: CO
Product: NC(=O)c1cc(O)ccc1[N+](=O)[O-]

Procedure:
Methyl 5-hydroxy-2-nitrobenzoate (48 g) in 340 ml methanol was heated 30 hours at 107° in a pressure vessel with 140 ml NH3. The mixture was cooled and concentrated to dryness on the rotovap. Water was added (200 ml) and the solid filtered and dried to give 12 g product, m.135-8°.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=1[O:32][CH3:33].C([O-])([O-])=O.[K+].[K+].[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44]>C(O)C.C(#N)C>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=4[O:32][CH3:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2noc3cc(Cl)ccc23)CC1
Yield: 71.9 %

Procedure:
A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 20 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 20 mmol), K2CO3 (2.8 g) and acetonitrile (120 ml) was refluxed for 16 hours. The reaction was allowed to cool, filtered, and the filtrate was concentrated to 9.9 g of a brown oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with methylene chloride/methanol (5%). Concentration of the appropriate fractions afforded 2:3 g of an off-white solid. The solid was dissolved in ethanol and fumaric acid (0.62 g, 1.1 eq.) was added. Upon concentration of the ethanol, a crude, brown solid was collected, which was taken up in refluxing acetone. Upon cooling, a white solid crystallized from solution yielding 2.2 g (19%) of 1-[4-[4-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone fumarate as a white solid, m.p.=139°-141° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[F:19][C:20]([F:40])([F:39])[C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:25](B(O)O)[CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:23]2[CH:22]=[C:21]([C:20]([F:40])([F:19])[F:39])[CH:26]=[CH:25][C:24]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(C)cc(C2=C(Br)CCC2)c1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Product: CCOC(=O)c1cc(C)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using [5-trifluoromethyl-2-(4-fluorobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid.
Reaction SMILES: COC1C=CC([C@@H]2O[C@H]2C(N)=O)=CC=1.C1(C)C(C)=CC=CC=1.NC1C=CC=CC=1S.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38][CH:39]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)[CH:40]([OH:44])[C:41]([NH2:43])=[O:42]>CO>[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38][C@@H:39]([C:45]1[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=1)[C@@H:40]([OH:44])[C:41]([NH2:43])=[O:42]
Reactant: COc1ccc(C(Sc2ccccc2N)C(O)C(N)=O)cc1
Agent: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Agent: Nc1ccccc1S
Solvent: Cc1ccccc1C
Solvent: CO
Product: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(N)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide (1.93 g) and xylene (15 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-aminothiophenol (1.38 g) and ferrous sulfate heptahydrate (0.28 mg) in methanol (0.2 ml) is added immediately into the reaction mixture, and the mixture is reacted at the same temperature for 5 minutes, and cooled to room temperature. The reaction mixture is subjected to HPLC analysis to confirm the production of 3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionamide (2.69 g, (2S,3S)/-(2S,3R)=91/9). The reaction mixture is concentrated under reduced pressure to remove the solvent, and the residue is dissolved with heating in ethanol (3 ml) and water (3 ml). The mixture is gradually cooled to 0° C. with stirring to crystallization. The precipitated crystals are collected by filtration, washed with chilled 50% ethanol, and dried at 50° C. to give (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionamide (0.84 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C:19]4([CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]4)[N:18]4[C@@H:13]([C:14](=[O:39])[O:15][C@@H:16]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C@H:17]4[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:12]3[C:40]3[CH:45]=[CH:44][N:43]=[C:42]([Cl:46])[C:41]=3[F:47])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-:49].[K+].[K+].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:12]([C:40]4[CH:45]=[CH:44][N:43]=[C:42]([Cl:46])[C:41]=4[F:47])[C@H:13]([C:14]([OH:49])=[O:39])[N:18]([C@H:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:16]([OH:15])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:19]43[CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1ccnc(Cl)c1F)[C@@]21C(=O)Nc2cc(Cl)ccc21
Reactant: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O
Product: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)O)[C@H](c1ccnc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
The compound (630 mg, 0.94 mmol) obtained in Step 1 of Example 16 was dissolved in acetonitrile (10 ml) and water (4 ml), potassium carbonate (130 mg, 0.94 mmol) was added and the resulting mixture was heated to reflux at 85° C. for 16 hours. After cooling, anhydrous magnesium sulfate (113 mg, 0.94 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. After extraction with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give (4′S,5′R)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-1′-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylic acid (650 mg, 100%) as a pale orange amorphous solid [MS (ESI) m/z: 688 (M+H)+.]. The carboxylic acid (650 mg, 0.94 mmol) obtained was dissolved in methanol (30 ml) and water (8 ml), cerium (IV) diammonium nitrate (1.55 g, 2.82 mmol) was added under ice cooling and the resulting mixture was stirred at the same temperature for 30 minutes. Potassium carbonate (780 mg, 5.64 mmol) was added under ice cooling and the resulting mixture was stirred at the same temperature for 1 hour. Insoluble matter was removed by filtration through celite, then the filtrate was concentrated under reduced pressure and water was added to the residue obtained, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=20:1→4:1 (v/v)] to give 152 mg (33%) of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([Si:3]([CH2:50][CH3:51])([CH:47]([CH3:49])[CH3:48])[O:4][CH:5]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH:14](O)[CH:13]=[CH:12][CH:11]([CH3:20])[CH:10](/[C:21](/[CH3:46])=[CH:22]/[CH:23]=[CH:24]/[C:25]([OH:45])([CH3:44])[CH2:26][CH:27]2[O:43][CH:28]2[CH:29]([CH3:42])[CH:30]([O:33][Si:34]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:31][CH3:32])[O:9][C:7](=[O:8])[CH2:6]1)[CH3:2].C(N(CC)CC)C.ClC([O:62][C:63]1[CH:68]=[CH:67][C:66]([N+:69]([O-:71])=[O:70])=[CH:65][CH:64]=1)=O.[C:72]([O:75]CC)(=[O:74])C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:50]([Si:3]([CH2:1][CH3:2])([CH:47]([CH3:48])[CH3:49])[O:4][CH:5]1[CH2:17][CH2:16][CH:15]([CH3:18])[CH:14]([C:72]([O:75][O:62][C:63]2[CH:64]=[CH:65][C:66]([N+:69]([O-:71])=[O:70])=[CH:67][CH:68]=2)=[O:74])[CH:13]=[CH:12][CH:11]([CH3:20])[CH:10](/[C:21](/[CH3:46])=[CH:22]/[CH:23]=[CH:24]/[C:25]([OH:45])([CH3:44])[CH2:26][CH:27]2[O:43][CH:28]2[CH:29]([CH3:42])[CH:30]([O:33][Si:34]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH:35]([CH3:36])[CH3:37])[CH2:31][CH3:32])[O:9][C:7](=[O:8])[CH2:6]1)[CH3:51]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCC(O[Si](CC)(CC)C(C)C)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)C(C)C)CCC(C)C(O)C=CC1C
Reactant: CCOC(C)=O
Agent: CCC(O[Si](CC)(CC)C(C)C)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)C(C)C)CCC(C)C(C(=O)OOc2ccc([N+](=O)[O-])cc2)/C=C/C1C
Agent: CCC(O[Si](CC)(CC)C(C)C)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)C(C)C)CCC(C)C(O)/C=C/C1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(O[Si](CC)(CC)C(C)C)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)C(C)C)CCC(C)C(C(=O)OOc2ccc([N+](=O)[O-])cc2)C=CC1C
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
A solution of (8E,12E,14E)-3,21-bis(diethylisopropylsiloxy)-7,16-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (271 mg, 0.3605 mmol), 4-dimethylaminopyridine (22 mg, 0.18 mmol) and triethylamine (369 mg, 3.61 mmol) in methylene chloride (5 mL) was cooled to 5° C. A solution of 4-nitrophenyl chloroformate (374 mg, 1.8 mmol) in methylene chloride (3 mL) was added dropwise to the solution, and the reaction mixture was stirred at 5 to 10° C. for one hour. The reaction mixture was diluted with ethyl acetate, and then the organic layer was washed with an aqueous solution of sodium hydrogencarbonate. The resulting organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:9->1:7->1:6) to obtain the title compound (319.6 mg, 97%) as a yellow pale oil.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCO
Temperature: -20 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a solution of 85.0 g (0.904 mole) of 1,5-pentanediol and 30.3 g (0.30 mole) of triethylamine in 350 mL of dry CH2Cl2 at -20° C. was added dropwise a solution of 28.5 g (0.25 mole) of methanesulfonylchloride in 100 mL of CH2Cl2 over 2 hours under nitrogen atmosphere. The solution was stirred at 2 hours at -20° C. and then at -4° C. for 18 hours. The reaction mixture was washed with H2O, 1N HCl, H2O, then dried and evaporated. The residual oil was chromatographed on a silica gel column, eluting with EtOAc-CH2Cl2 (2:8). After combining the appropriate fractions there was obtained 25.7 g (56.5%) of 5-hydroxypentylmethylsulfonate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.IC.[C:25]([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][CH:15]=3)[N:10]([CH3:25])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(=O)n(-c3cccc(Br)c3C)c(=O)[nH]c2c1
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(=O)n(-c3cccc(Br)c3C)c(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.7 %

Procedure:
A solution of 3-(3-bromo-2-methylphenyl)-7-methoxyquinazoline-2,4(1H,3H)-dione (440 mg, 1.22 mmol) in THF (30 mL) was treated with iodomethane (303 mg, 2.13 mmol) and Cs2CO3 (869 mg, 2.67 mmol) at room temperature. The mixture was stirred at room temperature overnight, then was filtered and concentrated. The residue was dissolved in DCM and washed sequentially with saturated aqueous NaHCO3 and water, dried and concentrated to give 3-(3-bromo-2-methylphenyl)-7-methoxy-1-methylquinazoline-2,4(1H,3H)-dione (502 mg), used without further purification. Mass spectrum m/z 375, 377 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.21 (d, J=8.8 Hz, 1H), 7.67 (dd, J=7.9, 1.3 Hz, 1H), 7.24-7.18 (m, 1H), 7.17-7.13 (m, 1H), 6.88 (dd, J=8.8, 2.2 Hz, 1H), 6.72 (d, J=2.2 Hz, 1H), 3.99 (s, 3H), 3.64 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C[Si](Cl)(C)C.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1.[NH3:37]>N1C=CC=CC=1.O>[N:37]#[N:10].[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([C@@:1]2([N:10]3[C:20]4[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=4[N:12]=[CH:11]3)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])=[O:35])=[CH:29][CH:28]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: N
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: c1ccncc1
Product: N#N
Product: Nc1nc2c(ncn2[C@]2(C(=O)Cc3ccc(Br)cc3)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Guanosine 5 (14.16 g, 50 mmoles) was dried three times by coevaporation with dried pyridine and suspended in 250 ml of dry pyridine. To this was added trimethylsilyl chloride (48 ml, 360 mmoles) at room temperature. After the solution was stirred for 1 hour at room temperature, 4-bromophenylacetyl chloride (35 g, 150 mmoles) was added dropwise and the solution stirred for 15 hours. The reaction mixture was then cooled in an ice bath and 75 ml of cold water was added. After 30 minutes 20 ml of 29% aqueous ammonia was added and the mixture stirred for 30 minutes. The solution was then evaporated to near dryness and the residue dissolved in 500 ml water and 500 ml methylene chloride. The product crystalized out of the solution upon extraction with CH2Cl2 was filtered off, washed with CH2Cl2 (3×70 ml) and ether (3×70 ml) and air dried to yield 14.4 g (60%) of Ribo GBPA 6c. The product was characterized as following: m.p. 160°-170° C. (dec.); UV (EtOH): λ max 280 nm and 258 nm; IR (KBr): ν 1688 (vs, br, C=O of amides), 3000-3500 (NH, OH) cm-1. 1H-NMR (DMSO-d6): δ 3.52 (m, 2H, C5, CH2), 3.67 (s, 2H, CH2C6H4), 3.91(m, 1H, C4, H), 4.14 (m, 1H, C3, H), 4.45(m, 1H, C2, H), 5.81 (t, 1H, J1',2' =5.64 Hz, C1, H), 7.15-7.56 (m, 4H, C6H4), 8.29 (d, 1H, C8H), 11.92 and 12.04 (2s, 2H, 2×NHCO).
Reaction SMILES: [OH:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[S:26](Cl)(Cl)=[O:27].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[O:1]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]2)[CH2:15][O:16][S:26]1=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CO)CC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)COS(=O)O2
Reaction time: 1 h
Yield: 117.1 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate (Bioorganic & Medicinal Chemistry Letters 2008, 18(21), 5804-5808) (400 mg, 1.73 mmol) and DIPEA (1.2 mL, 7.0 mmol) in THF (10 mL) cooled to 0° C. was added thionyl chloride (0.65 mL, 8.6 mmol) in a dropwise manner and the mixture was stirred at this temperature for 1 h. The mixture was then partioned with saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was extracted with ethyl acetate (3×) and the combined organic layers were washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated to afford 1,1-dimethylethyl 1,3-dioxa-2-thia-8-azaspiro[4.5]decane-8-carboxylate 2-oxide (562 mg) as an amber oil that was used without further purification. GC-MS (EI) for C11H19NO5S: 277 (M+).
Reaction SMILES: O1C=CC=[C:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)CO.S(Cl)([Cl:16])=O.[CH2:18]([O:20][CH2:21][CH3:22])[CH3:19]>>[O:20]1[CH:21]=[CH:22][CH:19]=[C:18]1[C:13]1[CH:12]=[CH:11][CH:8]=[CH:7][C:6]=1[CH2:2][Cl:16]
Reactant: O=S(Cl)Cl
Reactant: CCOCC
Reactant: OCc1cccc(-c2ccco2)c1
Product: ClCc1ccccc1-c1ccco1
Reaction time: 3 h

Procedure:
160 mg of the resulting alcohol compound was dissolved in 3 ml of anhydrous ethyl ether. Thionyl chloride (73 microliters) was added, and under ice cooling, the mixture was stirred for 3 hours. After the reaction, the reaction mixture was washed with a saturated aqueous solution of sodium chloride and 5% sodium hydrogen carbonate to give an ethyl ether solution of the captioned compound. It was used directly in the reaction of Example 58.