Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][N:14]=2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:38][C:39]([N:45]1[CH2:50][CH2:49][CH:48]([NH:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[CH:63][C:62]([C:65]([F:68])([F:67])[F:66])=[CH:61][CH:60]=3)=[CH:55][CH:54]=2)[CH2:47][CH2:46]1)([CH3:44])[C:40]([O:42][CH3:43])=[O:41]>CC(N(C)C)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:51]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:60]=[CH:61][C:62]([C:65]([F:67])([F:68])[F:66])=[CH:63][CH:64]=3)=[CH:55][CH:54]=2)[CH:48]2[CH2:49][CH2:50][N:45]([C:39]([CH3:38])([CH3:44])[C:40]([O:42][CH3:43])=[O:41])[CH2:46][CH2:47]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][N:14]=2
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)cc(=O)c2cccnc21
Reactant: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: COC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)cc(=O)c3cccnc32)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]acetic acid (Int. C2) (100 mg, 1 equiv), carbonyldiimidazole (50 mg, 1.05 equiv) and dimethylacetamide (4 ml) was stirred at 60° C. for 30 min then methyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B1) (132 mg, 1.05 equiv) was added and the temperature raised to 80° C. for 2 h. A further portion of carbonyldiimidazole (0.5 equiv) was added and stirring continued at 80° C. for 15 h. After cooling the crude mixture was applied to reverse phase HPLC (Preparative Method A) to obtain methyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1,8-naphthyridin-1(4H)-yl]acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate (99 mg).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH2:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:17][CH2:18][C:19]([NH:16][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:20]
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)NCCc1ccccc1

Procedure:
5 ml of triethylamine were added to a solution of 3.64 g of phenethylamine dissolved in 35 ml of methylene chloride, and the mixture was stirred, whilst ice-cooling. 2.63 ml of chloroacetyl chloride were then added dropwise to the mixture over a period of 5 minutes, after which it was stirred for 30 minutes whilst ice-cooling. The reaction mixture was then concentrated by evaporation under reduced pressure, after which ethyl acetate was added to the residue. The ethyl acetate solution was washed, in turn, with water, with a 5% w/v aqueous solution of sodium bicarbonate, with 10% w/v aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride. It was then dried, and the solvent was distilled off. The residue was recrystallized from a mixture of ethyl acetate and hexane, to give 4.96 g of the title compound as pale yellow-brown needles melting at 62°-65° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([CH2:18][OH:19])[C:11]=2[OH:20])=[C:4]([N+:21]([O-])=O)[CH:3]=1.[OH-].[Na+].C(S(O)=O)(N)=N.Cl>O.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][N:9]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([CH2:18][OH:19])[C:11]=3[OH:20])[N:21]=[C:4]2[CH:3]=1
Reactant: COc1cc(CO)c(O)c(N=Nc2ccc(F)cc2[N+](=O)[O-])c1
Agent: Cl
Agent: N=C(N)S(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(CO)c(O)c(-n2nc3ccc(F)cc3n2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
In a 500 ml round bottom flask equipped with a magnetic stirrer, liquid addition funnel, powder addition funnel, and nitrogen inlet was added 2-((4-fluoro-2-nitrophenyl)diazenyl)-6-(hydroxymethyl)-4-methoxyphenol from Example 5 part I and 200 ml ethanol. NaOH (21.7 g, 542 mmol) pellets (97+%, A.C.S. reagent, Aldrich) were dissolved in 100 ml deionized water and approximately one-fourth of the solution was added dropwise to the reaction mixture. The mixture was subsequently heated to 80° C. and 29.3 g (271 mmol) formamidinesulfinic acid (Aldrich) and the remaining sodium hydroxide solution were concurrently added to the reaction mixture over 30 minutes. The mixture was stirred at 80° C. for 3 hours and the contents were then poured into 3 L deionized water and acidified to pH 4 using 1N HCl. The solid was collected by filtration, suspended in 300 ml methanol, and stirred for 30 minutes while cooling to below −20° C. The solid was collected by filtration and then suspended in 300 ml ethanol, cooled again to below −20° C., filtered, and then dried to afford 7.8 g (30%) of a yellow solid, which was used in the next esterification step.
Reaction SMILES: [Br-].C(CCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.[Na].[H-].[Na+].C(OC([N:38]1[CH2:42][C@H:41]([NH:43][S:44]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[CH2:40][C@H:39]1C=O)=O)(C)(C)C>CS(C)=O.O>[Cl:53][C:50]1[CH:49]=[CH:48][C:47]([S:44]([NH:43][CH:41]2[CH2:42][NH:38][CH2:39][CH2:40]2)(=[O:46])=[O:45])=[CH:52][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C[C@H]1C=O
Agent: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(NC1CCNC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 225.2 %

Procedure:
To a solution of (4-carboxybutyl)triphenylphosphonium bromide (17.3 g) in dimethyl sulfoxide (45 ml) was added sodium methylsulfinylmethide [78.0 m mol, prepared from sodium hydride (3.12 g) and dimethyl sulfoxide (45 ml)] and the solution was stirred at room temperature for 20 minutes. To the resulting solution was added (2S,4R)-1-t-butoxycarbonyl-4-(4chlorophenylsulfonylamino)-2-formylpyrrolidine (5.06 g) in dimethyl sulfoxide (30 ml) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water and the aqueous solution was washed with ethyl acetate. The aqueous phase was adjusted to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of chloroform and methanol (40:1) as an eluent to give (2S,4R)-1-t-butoxycarbonyl-2-[(E and Z)- 5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonylamino) pyrrolidine (7.64 g) as a pale brown oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][N:15]=[CH:14]3)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:21](OCCC(C)C)=O>CN(C=O)C.CO>[Br:1][C:2]1[N:3]=[C:4]2[N:9]([CH2:10][C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]=[CH:14]4)[N:21]=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)nc1NCc1ccc2ncncc2c1
Reactant: CC(C)CCON=O
Solvent: CN(C)C=O
Solvent: CO
Product: Brc1cnc2nnn(Cc3ccc4ncncc4c3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
To the solution of 5-bromo-N*3*-quinazolin-6-ylmethyl-pyrazine-2,3-diamine (1.02 g) in anhydrous DMF (12 mL) was added isoamyl nitrite (0.5 mL, 1.2 eq) at 0° C. dropwise. The ice bath was removed and the mixture was stirred for 5 minutes at room temperature, then at 70° C. for three hours. The reaction was cooled down to ambient temperature and quenched by 3 ml Sat'd Na2SO3. A precipitate was formed, and filtered. The mother liquor was extracted with ethyl acetate (2×200 ml) twice, and the combined extracts were washed twice by Sat'd NaHCO3 (2×100 ml), dried over Na2SO4, and concentrated to get the crude product which was dissolved in MeOH (10 ml), and a precipitate was formed. The solid was filtered to get 6-(6-Bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-quinazoline (0.112 g, yield 13%).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:10]=[C:11]([C:12]#[N:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:25]1[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[C:12]([C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:25]3[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=2)[CH:10]=1)#[N:13]
Reactant: C#Cc1cnc2c(C#N)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3ccc(S(N)(=O)=O)s3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-8-carbonitrile (example C.23) (150 mg, 0.5 mmol) and commercially available 5-bromothiophene-2-sulfonamide (117 mg, 0.5 mmol) according to general procedure II. Obtained as an off-white solid (80 mg, 35%). MS (ISP) 473.1 [(M+H)+]; mp 267-269° C.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:36][C:28]1[CH:29]=[CH:30][C:31]([N+:33]([O-:35])=[O:34])=[CH:32][C:27]=1[C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])ccc1F

Procedure:
1.126 ml of ethynyl(trimethyl)silane, 55 mg of triphenylphosphine and 24 mg of palladium (2+) acetate are added to a solution of 1.169 g of 2-bromo-1-fluoro-4-nitrobenzene in 13 ml of triethylamine with stirring and under argon. After four and a half hours at a temperature of 100° C., the reaction medium is cooled and the insoluble material is filtered off through sintered glass. The filtrate is concentrated to dryness under reduced pressure. After two silica column purifications, eluent: 90/10 heptane/EtOAc then 95/5 heptane/EtOAc, 460 mg of [(2-fluoro-5-nitrophenyl)ethynyl](trimethyl)silane are obtained in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]2[O:24][CH3:25])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][C:16]([CH3:22])([CH3:23])[CH:15]2[O:24][CH3:25]
Reactant: CCN1CC(C)(C)C(OC)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN1CC(C)(C)C(OC)c2cccc(CO)c21
Reaction time: 0.75 h
Yield: 78.1 %

Procedure:
To a solution of 8-(t-butyldimethylsilyloxymethyl)-4-methoxy-3,3-dimethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (1.40 g) in tetrahydrofuran (20 ml), 1M solution (4.2 ml) of tetrabutylammonium fluoride in tetrahydrofuran was added dropwise under ice-cooling. After the mixture was stirred for 45 minutes, tetrahydrofuran was distilled off and the residue was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent:n-hexane-ethyl acetate (6:1)] to give 8-hydroxymethyl-4-methoxy-3,3-dimethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (0.75 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([CH2:17][CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH2:11][C:12]#[C:13][C:14](=[O:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCOCC.CCCCCC>ClC1C=CC=CC=1Cl>[Si:1]([O:8][CH2:9][C:10]1([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:17][C:18]2=[CH:19][C:20]3[C:25]([C:13]([C:14](=[O:16])[CH3:15])=[C:12]2[CH2:11]1)=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(=O)C#CCC(CC=Cc1ccccc1Cl)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Solvent: Clc1ccccc1Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)c1c2c(cc3c(Cl)cccc13)CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)C2
Yield: 92 %

Procedure:
To a 2-5 mL microwave irradiation vial equipped with a stir bar was added compound 4c (0.09 g, 0.17 mmol) in 1,2-dichlorobenzene (3 mL). The reaction was irradiated with stirring at 180° C. for 45 min until complete by TLC (Et2O/n-hexane 1:9). The solution was directly added to a silica gel column, which was eluted with n-hexane to separate the 1,2-dichlorobenzene and then Et2O/n-hexane 2:8 to collect the pure product. The title compound was isolated as a light yellow oil in a 92% yield (0.083 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:44][C:45]([N:47]([CH3:49])[CH3:48])=[O:46]>CN(C)C=O.C(OCC)(=O)C>[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH2:44][C:45]([N:47]([CH3:49])[CH3:48])=[O:46])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:14])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C(=O)CCl
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)COc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Potassium carbonate (246 mg, 1.78 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (310 mg, 0.59 mmol) in N,N-dimethylformamide (2 mL) at room temperature and stirred for 30 min. 2-Chloro-N,N-dimethyl-acetamide (0.061 mL, 0.59 mmol) was then added to the above mixture and stirred at room temperature for 13 h. The mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-N,N-dimethyl-acetamide (340 mg, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C31H33N3O6S2 [M+H]+ 608.75, observed 608.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1)([O-:3])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.[Cl-].[Na+].O>[Cl:25][C:8]1[N:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnn(C2CCOCC2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cnn(C2CCOCC2)c1Cl
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
To a solution of 4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (1 equiv) in THF (0.5 M) was added dropwise a 1.0M solution of lithium bis(trimethylsilyl)amide (14 equiv) in THF at −78° C. The reaction was stirred at −78° C. for 30 min before hexachloroethane (1.5 equiv) in THF (1.15 M) was added. The reaction was stirred at −78° C. for 2.5 h then warmed to room temperature. The reaction was diluted with brine (0.23 M) and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (10-20% ethyl acetate in petroleum ether) to afford the desired product (81% yield) as a white solid. MS (ESI) m/z 232.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])(=[O:4])=[O:3].[CH3:17][NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([O:27][CH3:28])[N:20]=1>C(Cl)Cl>[CH3:26][O:25][C:23]1[N:22]=[C:21]([O:27][CH3:28])[N:20]=[C:19]([N:18]([CH3:17])[C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:3])=[O:4])(=[O:12])=[O:13])=[O:16])[N:24]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CNc1nc(OC)nc(OC)n1
Solvent: ClCCl
Product: COc1nc(OC)nc(N(C)C(=O)NS(=O)(=O)c2ccccc2S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of 2-methylsulfonylbenzenesulfonylisocyanate (2.1 g, 8.0 mmol) in dry methylene chloride (12 ml) was added to 2-methylamino-4,6-dimethoxy-1,3,5-triazine (1.0 g, 6.0 mmol) and a catalytic amount of 1,4-diaza[2.2.2]bicyclooctane. The mixture was stirred at room temperature overnight. The solvent was removed in-vacuo and 1-chlorobutane was added to the residue. The precipitated solid was filtered and dried to give N-[(4,6-dimethoxy-1,3,5-triazin-2-yl)(methyl)aminocarbonyl]-2-(methylsulfonyl)benzenesulfonamide (2.3 g) as a white powder, m.p. 160°-162.5°. The product showed characteristic singlets in the NMR at δ3.25 (NCH3), 3.40 (SO2CH3) and 4.0 (OCH3), and showed infrared absorption peaks at 1690, 1550, 1420, 1340, 1310 and 1150 cm-1.
Reaction SMILES: C([O:24][CH:25]([CH2:44][OH:45])[CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])(=O)/C=C\C=CC=CC=CC=CC=CCCCCCCCCC>Cl>[CH2:28]([O:27][CH2:26][CH:25]([CH2:44][OH:45])[OH:24])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=C/C=C\C(=O)OC(CO)COCCCCCCCCCCCCCCCC
Agent: Cl
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To compound 1a (3.363 g) was added 10% HCl solution (40 mL) and refluxed at 120° C. for 30 min. The reaction mixture was then kept at RT for 24 hours. The white lumps formed were filtered. The filtrate was extracted with hexane (50 mL, 2×) and the extracts added to the white lumps after removal of solvent. It was dried in a vacuum dessicator for 24 hours to obtain 2a which was quantitative. 1H NMR (in CDCl3): δ in ppm 0.83-0.87 (3H, m), 1.23 (26H, m), 1.52-1.55 (2H, m), 2.67 (1H, D2O exchangeable), 3.42-3.51 (4H, m), 3.60-3.70 (2H, m), 3.84-3.85 (1H, m), 6.63-6.70 (1H, D2O exchangeable); 13C NMR (in CDCl3): δ in ppm 14.6, 23.1, 26.5, 29.8, 29.9, 30.0, 30.1, 30.2, 32.4, 64.5, 71.0, 72.3, 72.9.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:26]=1)/[CH:5]=[C:6]1/[C:7](=[O:23])[C:8]2[C:13]([CH2:14]/1)=[CH:12][C:11]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[C:10]([O:21][CH3:22])[CH:9]=2>CO.[Pd]>[CH3:22][O:21][C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH:6]([CH2:5][C:4]3[CH:3]=[CH:2][CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=3)[C:7]2=[O:23])=[CH:12][C:11]=1[N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(Br)cc(OC(F)(F)F)c1)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1cccc(OC(F)(F)F)c1)C2=O
Reaction time: 6 h

Procedure:
To a solution of compound 13 (150 mg, 0.607 mmol) in toluene 15 mL was added 3-bromo-5-(trifluoromethoxy)benzaldehyde 29 (115.4 mg, 0.607 mmol). PTSA (230.9 mg, 1.214 mmol) was added to the reaction mixture, then stirred at 120° C. for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound (E)-2-(3-bromo-5-(trifluoromethoxy)benzylidene)-6-methoxy-5-morpholino-2, 3-dihydro-1H-inden-1-one 30, which was purified through flash chromatography by using 100-200 mesh silica gel. Compound 30 was eluted at 25% ethyl acetate in hexane to afford a yellow coloured solid. To 30 (45 mg, 0.107 mmol), dissolved in methanol 20 mL, was added Pd/C 20 mg and stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude des-brominated compound 31. The crude 31 was purified by flash chromatography using 100-200 mesh silica gel. Compound 31 was eluted as des-brominated compound at 25% ethyl acetate in hexane as half white coloured solid compound 6-methoxy-5-morpholino-2-(3-(trifluoromethoxy)benzyl)-2,3-dihydro-1H-inden-1-one 31. 1HNMR (400 MHz, CDCl3) δ ppm 7.43 (m, 4H), 7.18 (s, 1H), 6.81 (s, 1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.43 (m, 1H), 3.17 (m, 4H), 3.06 (m, 1H), 2.97 (m, 1H), 2.69 (m, 2H); MS (ESI) m/z 422.1 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][N:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:27]2[S:28][CH:29]=[C:30]([CH:32]=O)[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:32][C:30]2[N:31]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:28][CH:29]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1csc(-c2ccccc2)n1
Reactant: COC(=O)CCCCC(N)c1c(OC)cncc1OC
Product: COc1cncc(OC)c1C1CCCCC(=O)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(3,5-dimethoxypyridin-4-yl)hexanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 423.86 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[C:12]([O:14]C(=O)C3C=CC=CC=3)([CH3:13])[CH:11]([O:23]C(=O)C3C=CC=CC=3)[CH:10]([CH2:32][O:33]C(=O)C3C=CC=CC=3)[O:9]2)[C:4](=[O:42])[N:3]=1.C[O-].[Na+].CO>>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[C:12]([OH:14])([CH3:13])[CH:11]([OH:23])[CH:10]([CH2:32][OH:33])[O:9]2)[C:4](=[O:42])[N:3]=1
Reactant: CC1(OC(=O)c2ccccc2)C(OC(=O)c2ccccc2)C(COC(=O)c2ccccc2)OC1n1ccc(N)nc1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(O)C(O)C(CO)OC1n1ccc(N)nc1=O

Procedure:
In one synthesis method, depicted in FIG. 1a, the synthesis comprises reacting cytosine, BSA and SnCl4/acetonitrile with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (1) to form 4-amino-1-(3,4-dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (2); and reacting (2) with NaOMe/MeOH to provide 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (3), also known as 2-C-methyl-β-D-ribofuranose. The use of cytosine as a starting material rather than benzoyl-cytosine improves the “atom economy” of the process and simplifies purification at later steps.