Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][OH:10].N1C=CC=CC=1.C[Si](C)(C)Cl.[Cl:22][CH2:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>C(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]([OH:10])[C:25](=[O:26])[C:24]([CH3:29])([CH3:28])[CH2:23][Cl:22]
Reactant: ONCc1ccccc1Br
Reactant: CC(C)(CCl)C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(CCl)C(=O)N(O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
Under an argon atmosphere a stirred solution of 8.8 grams (0.044 mole) of N-(2-bromophenylmethyl)hydroxylamine and 12.0 grams (0.152 mole) of pyridine in 200 ml of methylene chloride was cooled to -10°. The reaction vessel was fitted with a septum and 5.2 grams (0.048 mole) of trimethylchlorosilane was added in small portions from a hypodermic syringe. Upon completion of addition the reaction mixture was stirred at -10° for 30 minutes, then allowed to warm to 0°. At this temperature a solution of 6.7 grams (0.044 mole) of 3-chloro-2,2-dimethylpropionyl chloride (prepared in the manner of Example 1, Step B) in 5 ml of methylene chloride was added dropwise over a 20-minute period. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred for 18 hours. The reaction mixture was poured into a separatory funnel and diluted with 50 ml of methylene chloride. The mixture was washed with 50 ml of water, 50 ml of an aqueous solution saturated with sodium chloride, two portions of 100 ml each of a solution consisting of 1:1--aqueous saturated sodium chloride solution:aqueous 10% hydrochloric acid solution, and finally 50 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a semi-solid residue. The semi-solid was slurried in 15 ml of hexane. The insoluble material was collected by filtration and recrystallized twice from hexane/ethyl acetate to give 5.7 grams of N-(2-bromophenyl)methyl-3-chloro-N-hydroxy-2,2-dimethylpropanamide; mp 119°-121°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[O:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[ClH:16].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:28][C:29]([CH3:32])=[N:30][N:31]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Product: Cc1nnc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Product: Cl

Procedure:
The title compound was prepared according to Procedure A from 4-benzyloxyaniline and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.73(1H,bs), 9.41(1H,s), 8.90(1H,s), 8.58(1H,d), 8.10(1H,d), 7.65(2H,d), 7.40(5H,m), 7.15(2H,d), 5.19(2H,s), 2.65(3H,s); m/z (M+1+) 410.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([S:25](Cl)(=[O:27])=[O:26])=[C:20]([CH3:29])[CH:19]=1.Cl>ClCCl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:29])[C:21]([S:25]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:7][OH:8])(=[O:26])=[O:27])=[C:22]([CH3:24])[CH:23]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: OC[C@@H]1CCCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2CO)c(C)c1
Reaction time: 1.5 h
Yield: 20 %

Procedure:
(S)-Piperidin-2-ylmethanol (1.1 eq.) was dissolved in dichloromethane (4 ml/mmol) and cooled, and triethylamine (2.5 eq.) was added. A solution of 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (1 eq.) in dichloromethane (2 ml/mmol) was added dropwise at 0° C., and then stirring was carried out for 90 min at room temperature. Hydrogen chloride solution (eq., 0.5 mol/l, 2 ml/mmol) was added, stirring was carried out for 15 min, and the phases were separated. The organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was used in the next stage without being purified further. Yield: 20%
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.I[CH2:15][C:16]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17]2.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:16]12([CH2:15][N:1]3[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]3)[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17]2
Reactant: ICC12CCC(CC1)O2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(CC23CCC(CC2)O3)C1
Temperature: 75 °C
Reaction time: 32 h
Yield: 52.3 %

Procedure:
The mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (500 mg), 1-(iodomethyl)-7-oxabicyclo[2.2.1]heptane (639 mg) and K2CO3 (742 mg) in DMF (5 mL) was stirred at 75° C. for 32 hours. The resultant was added H2O, extracted with AcOEt. The organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-1-(7-oxabicyclo[2.2.1]hept-1-ylmethyl)-3-pyrrolidinyl]carbamate (416 mg) as orange oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[O:23])[CH:17]=2)=[C:11]([CH3:24])[C:10]=1[Cl:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO.[BH4-].[Na+].O>O1CCCC1>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=2)=[C:11]([CH3:24])[C:10]=1[Cl:25])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)c(Cl)c(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)c(Cl)c(C)c1-c1cccc(CO)c1
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of 4′-{[tert-butyl(dimethyl)silyl]oxy}-3′-chloro-2′,6′-dimethylbiphenyl-3-carbaldehyde (1.78 g, 4.75 mmol) in a mixed solvent of in tetrahydrofuran (10 mL) and methanol (5 mL) was added sodium borohydride (90%, 90 mg, 2.38 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 2 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60) to give the title compound (1.74 g, yield 97%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.CS(O[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:25][CH:26]=2)=[CH:16][CH:15]=1)(=O)=O>>[C:29]1(/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:20][C:17]3[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][N:2]4[N:3]=[CH:4][CH:5]=[N:1]4)=[CH:19][CH:18]=3)[N:23]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1c[nH]nn1
Product: C(=C/c1nc(COc2ccc(CCCn3nccn3)cc2)co1)\c1ccccc1
Yield: 35 %

Procedure:
In substantially the same manner as in Working Example 8, 1,2,3-triazole was allowed to react with 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate. The reaction mixture was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:1, v/v), 2-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2H-1,2,3-triazole was obtained. The yield was 35%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 103-104° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][C:32](Cl)=[O:33]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:32](=[O:33])[CH2:31][C:27]3[S:26][CH:30]=[CH:29][CH:28]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1
Product: O=C(Cc1cccs1)Nc1ccccc1CCCN1CCN(c2nsc3ccccc23)CC1

Procedure:
N-{2-[3-(4-1,2-Benzoisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-thiophen-2-yl-acetamide was prepared according to the procedure outlined in Example 1, starting with 2-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenylamine (200 mg) and 2-thiopheneacetyl chloride (0.069 mL). The resultant white solid was purified using an ISCO autocolumn eluting with 80% ethyl acetate in hexanes. N-{2-[3-(4,1,2-Benzoisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-(4-chloro-phenyl)-acetamide was isolated in 100% purity @ 254 nm; LCMS (APCI): 477 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:5]([C:7](Cl)=[O:8])[N:6]=1.[Br:17][C:18]1[C:26]2[N:25]=[C:24]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]3)[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[Br:17][C:18]1[C:26]2[N:25]=[C:24]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][C:4]=3[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[O:8])[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: Brc1cccc2[nH]c(CC3CCCCN3)nc12
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(Br)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Yield: 89 %

Procedure:
2-Methyl-5-(4-fluorophenyl)thiazole-4-carbonyl chloride (383 mg, 1.5 mmol) was added portionwise over 5 min. to a stirred solution of (RS)-4-bromo-2-piperidin-2-ylmethyl-1H-benzoimidazole, D39 (400 mg, 1.4 mmol) and triethylamine (0.57 ml, 5.0 mmol) in dichloromethane (20 ml) at room temperature. After 20 h the mixture was washed with saturated sodium hydrogen carbonate. The organic layer was dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 10-100% ethyl acetate-hexane then 1-10% methanol-ethyl acetate) afforded the title compound as a pale brown amorphous solid (620 mg, 89%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH2:12][N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)=[CH:27][CH:26]=3)[CH2:16][CH2:15][C:14]2=[O:48])=[O:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:56](OC(=O)C)(=[O:58])[CH3:57]>ClCCl.CN(C)C1C=CN=CC=1>[C:56]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH2:12][N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)=[CH:27][CH:26]=3)[CH2:16][CH2:15][C:14]2=[O:48])=[O:11])[CH2:6][CH2:5]1)(=[O:58])[CH3:57]
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CC(=O)N4CCN(CCO)CC4)c4ccccc43)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCN1CCN(C(=O)CN2C(=O)CCN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccc(C)cc4)cc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.1 %

Procedure:
To a solution of 1-[[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl}-5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (178 mg) and triethylamine (31 mg) in dichloromethane (4 ml) was added acetic anhydride (31 mg) and the mixture was stirred at ambient temperature for 1.5 hours. To the mixture was added 4-dimethylaminopyridine (10 mg) and acetic anhydride (10 mg), and then the mixture was stirred at ambient temperature for 15 minutes. The resulting mixture was diluted with dichloromethane and the organic layer was washed successively with saturated aqueous sodium bicarbonate solution and brine. Drying, filtering and the removal of solvents afforded a crude product. The crude product was triturated with a mixture of diethyl ether and n-hexane (1:1) to give 1-{[4-(2-acetoxyethyl)-1-piperazinyl]-carbonylmethyl)-5-{4-[2-(4-methylphenyl)benzoylamino]-benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (205 mg) as a slightly-yellow powder.
Reaction SMILES: Cl[CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CO>[NH3:5].[CH:12]1[C:13]2[C:8](=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][CH:14]=2)[CH:9]=[CH:10][N:11]=1
Reactant: O=C(Nc1ccc2cnccc2c1)C(Cl)c1ccccc1
Reactant: C1COCCN1
Solvent: CO
Product: N
Product: O=C(Nc1ccc2cnccc2c1)C(c1ccccc1)N1CCOCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 2-chloro-2-phenyl-N-(isoquinolin-6-yl)acetamide (E39) in MeOH is added KI and the solution is heated to 60° C. for 40 minutes. The mixture is cooled to 45° C. and morpholine is added and stirred at 45° C. After 2-4 hours, the solvents are evaporated and the residue is taken up in EtOAc and extracted with NaHCO3(sat). The organics are dried (Na2SO4), filtered and evaporated. Flash chromatography (2% NH3(2M/MeOH/3% MeOH/CH2Cl2) gives N-(isoquinolin-6-yl)-2-morpholino-2-phenyl-acetamide (E39a).
Reaction SMILES: [Br:1][CH:2]([C:4]1[N:5]=[C:6]2[S:13][CH:12]=[CH:11][N:7]2[C:8](=[O:10])[CH:9]=1)[CH3:3].[Br:14]N1C(=O)CCC1=O>C(#N)C>[Br:14][C:9]1[C:8](=[O:10])[N:7]2[CH:11]=[CH:12][S:13][C:6]2=[N:5][C:4]=1[CH:2]([Br:1])[CH3:3]
Reactant: CC(Br)c1cc(=O)n2ccsc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(Br)c1nc2sccn2c(=O)c1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A mixture of 7-(1-bromo ethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (17.5 g, 67.5 mmol) and N-bromosuccinimide (14.2 g, 79.8 mmol) in acetonitrile (400 mL) was stirred at 80° C. under N2 overnight. After removal of the solvent under reduced pressure, the resulting solid was dissolved in dichloromethane, washed sequentially with water, saturated aqueous Na2S2O3 and NaHCO3 solution and brine, dried over Na2SO4, and then concentrated to give crude product (3.7 g), which was used in the next step without further purification. LCMS calculated for C8H7Br2N2OS (M+H)+: m/z=336.9. Found: 336.9.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:95]=[CH:94][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][C@@H:73]([S:91][S:92][CH3:93])[CH2:74][CH2:75][C@H:76]([NH:83][C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C:77](OCC#N)=[O:78])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]>C(#N)C>[N:60]([C:63]1[CH:64]=[CH:65][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][C@H:73]([S:91][S:92][CH3:93])[CH2:74][CH2:75][C@@H:76]([NH:83][C:84]([O:86][C:87]([CH3:89])([CH3:90])[CH3:88])=[O:85])[C:77]([O:40][C@H:39]2[C@@H:38]([OH:41])[C@@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36][C@H:35]2[CH2:34][O:33][P:30]([O:29][C@H:28]2[CH2:27][C@H:26]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:25][C@@H:24]2[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:78])=[O:70])=[CH:94][CH:95]=1)=[N+:61]=[N-:62]
Reactant: CSS[C@@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N)CNC(=O)OCc1ccc(N=[N+]=[N-])cc1
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CSS[C@H](CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O)CNC(=O)OCc1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (49.2 mg, 0.077 mmol) and (2S,5S)-cyanomethyl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk9) (125 mg, 0.232 mmol) in acetonitrile (0.5 mL) was added to buffer A (13 mL), and the mixture was stirred at room temperature for 2 hours. Acetonitrile (0.5 mL) was added and the mixture was stirred for 1.25 hours, followed by addition of acetonitrile (0.5 mL). After stirring for a further 1.25 hours, acetonitrile (0.5 mL) was added and the mixture was stirred for 1.5 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S,5S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk10) (14.0 mg, 16%).
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[Cl:9][C:10]1[C:11](=[O:24])[CH:12]=[CH:13][C:14]2[C:23]=1[S:22][C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[N:15]=2>O.CN(C=O)C>[Cl:9][C:10]1[C:23]2[S:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:24]
Reactant: O=c1ccc2nc3ccccc3sc-2c1Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1Cl)Sc1ccccc1N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A solution of Na2S2O4 (70 g) in water (500 ml) was added to a solution of 4-chloro-3H-phenothiazin-3-one (50 g) in DMF (1200 ml). The reaction mixture was stirred at room temperature for 3 hours and then poured in 5 liters of water. The resulting precipitate was then filtered to give the 4-chloro-3-hydroxy-10H-phenothiazine (95 %). m.p.: 110° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[H-].[Na+].I[CH3:17]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:17])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2c([N+](=O)[O-])cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
6-Bromo-4-nitro-1H-indazole (available from Sinova, 1.05 g, 4.13 mmol) was dissolved in THF (20 ml) and cooled to 0° C. under nitrogen. 60% Sodium hydride in mineral oil (191 mg, 7.57 mmol) was added portion-wise allowing the evolution of gas to subside before adding the next portion. This was left under nitrogen, stirring at 0° C. for 15 mins. Iodomethane (0.298 ml, 4.78 mmol) in THF (5 ml) was added dropwise to the reaction, washing through with further THF (5 ml). The reaction was then allowed to warm to room temperature. The reaction was stirred for 5 h then partitioned between ethyl acetate and water, washing the water with ethyl acetate (x3). The combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by silica chromatography using a gradient of 0-25% ethyl acetate in cyclohexane, to give the title compound (388 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.CC1C=CC(S(O[CH2:24][C@@H:25]2[O:27][CH2:26]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:12])[C:5]([O:11][CH2:24][CH:25]2[CH2:26][O:27]2)=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CC(=O)c1cc(Br)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Br)cc(Cl)c1OCC1CO1
Temperature: 60 °C
Yield: 74.7 %

Procedure:
A mixture of 1-(5-bromo-3-chloro-2-hydroxyphenyl)ethanone (5.5 g, 21.9 mmol), (2R)-(−)Glycidyltosylate (10 g, 43.8 mmol) and K2CO3 (4.5 g, 32.9 mmol) in DMF (25 ml) was heated at 60° C. for 25 h. The solution was brought to ambient temperature and water and EtOAc was added. The water phase was extracted with EtOAc. The combined organic phases were washed with LiCl (5%), HCl (1 N) and brine and then dried (Na2SO4) and evaporated to dryness. Purification on flash column chromatography (isooctane/EtOAc) gave the title compound (5.0 g). MS m/z (rel. intensity, 70 eV) 250 (30), 248 (M+, 26), 235 (bp), 233 (85), 57 (90), 306 (M+, 9).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:21]CC2C=CC=CC=2)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1.B(Br)(Br)Br.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][N:10]=1
Reactant: FC(F)(F)c1cnc(Oc2c(Cl)cc(OCc3ccccc3)cc2Cl)c(Cl)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Oc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Yield: 92.7 %

Procedure:
Then, 1.39 g of 3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1-benzyloxybenzene and 20 ml of methylene chloride were charged into a reaction vessel, and a solution of boron tribromide (1.63 g) in methylene chloride (10 ml) was added dropwise with stirring under ice cooling (-10° C. to 0° C.). After stirring for one hour under ice cooling, the mixture was poured into 10% hydrochloric acid and extracted twice with 50 ml of methylene chloride. Then, the organic layers were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to give a crude product. This crude product was subjected to silica gel column chromatography to give 1.03 g of 3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenol (yield, 93%), m.p., 152.6° C.
Reaction SMILES: [CH2:1]([C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18])[CH2:2][CH2:3][CH:4]=C.C[N+]1([O-])CC[O:23]CC1.O1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH:4]([CH2:3][CH2:2][CH2:1][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18])=[O:23]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCCCC12CCCc3cccc(c31)NC2=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=CCCCC12CCCc3cccc(c31)NC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a shaded container, 2a-(4-pentenyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (1.3 g, 5.3 mmol) and N-methylmorpholine oxide (1.9 g, 16 mmol) were dissolved in a mixed solvent of 1,4-dioxane (20 ml) with water (10 ml), and the solution was mixed with osmium tetroxide (4% aqueous solution 3.4 ml, 0.53 mmol) and stirred at room temperature for 2 hours. The reaction solution was mixed with rater (80 ml), the reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure. The residue was dissolved in a mixed solvent of 1,4-dioxane (20 ml) with water (10 ml), and the solution was mixed with sodium periodate (2.6 g, 12 mmol) and stirred as such for 2.5 hours. The reaction solution was mixed with water (100 ml), and the reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. By evaporating the solvent from the extract under a reduced pressure, 1.3 g (5.3 mmol 100% in yield) of the title compound was obtained.