Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].CS(O)(=O)=O.C([Si](C=C)(C)O[Si](C)(C)C)=C>[Pt].C1(C)C=CC=CC=1>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCC
Reactant: CCO[SiH](OCC)OCC
Agent: [Pt]
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Yield: 88 %

Procedure:
Reaction between octene-1 and triethoxysilane with platinum catalyst in the presence of trimethylsilyl ester of methanesulfonic acid. 325 mg Octene-1 and 475 mg triethoxysilane were introduced into a glass tube filled with argon gas, and 20 mg of a trimethylsilyl ester of methanesulfonic acid and 0.002 ml (1.7 mg) of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (0.04 wt % platinum content) were added. The tube was sealed with Teflon tape and a rubber septum, degassed, and then filled again with argon gas. The tube was placed in a 75° C. oil bath where it was heated for 1 hour. After cooling, the tube contents were analyzed by gas chromatography revealing an octyltriethoxysilane yield of 88%.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]1[CH:20]=O)=[O:6])[CH:2]=[CH2:3].C(O)C.[C:25]1([NH2:35])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>C(O)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]1[CH2:20][NH:35][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1C=O
Reactant: Nc1cccc2ccccc12
Solvent: CC(=O)O
Solvent: CCO
Product: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CNc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.1 %

Procedure:
A mixture of (2S,4S)-2-formyl-4-BOCsulfanyl-pyrrolidine-1-carboxylic acid allyl ester (compound(1)) ( 711 mg), ethanol(25 ml), 1-naphthylamine(333 mg) and 3A molecular sieves(4.5 g.) was stirred under an argon atmosphere at ambient temperature for 6 hours. Acetic acid (0.4 ml) was added followed by sodium cyanoborohydride(l70 mg). The mixture was then stirred for a further 20 hours when the sieves were removed by filtration. The filtrate was concentrated under reduced pressure and the residue applied to a silica column and eluted with ethyl acetate/hexane(20:80) to give (2S,4S)-1-allyloxycarbonyl-2[(naphthalen-1-ylamino)-methyl]-4-BOCsulfanylpyrrolidine (compound(31)) as a clear oil (560 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][O:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Reaction time: 24 h

Procedure:
Methanesulfonyl chloride (4.0 mL, 52 mmol) was added slowly to a 0° C. solution of 1-t-butyloxycarbonyl-4-hydroxyethylpiperidine (10.0 g, 43.7 mmol) and diisopropylethylamine (7.3 mL, 52 mmol) in dichloromethane (100 mL) with stirring under a nitrogen atmosphere. After 24 hours at room temperature, the mixture was extracted with water (4×100 mL), dried (MgSO4), filtered, and concentrated in vacuo to yield a clear oil which crystallized upon standing. Mp:60°-63° C. MSCI:252(MH+, base). 1H NMR(300 MHz, CDCl3 /TMS, δ): 4.3(br t,2H), 4.1(br d,2H), 3.0(S,3H), 2.7(br t,2H), 1.7-1.1(m,16H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 38976.4 %

Procedure:
A mixture of 2-chloronicotinic acid (20 g, 0.127 mmol) and oxalyl chloride (13.3 mL, 0.152 mmol) in 2 drops of DMF and 200 mL of methylene chloride was stirred at room temperature for approximately 14 hours. The mixture was stirred at reflux temperature for 1 hour. The solution was cooled and partitioned between 100 mL of ice-cold aqueous sodium bicarbonate and 300 mL of methylene chloride. The organic layer was washed with brine, dried (Na2SO4) and concentrated to give 2-chloronicotinic acid chloride (8.8 g, 49.5 mmol).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (3.0 g, 21 mmol) in DMSO (30 mL) was added ethyl piperidine-4-carboxylate (5.0 g, 32 mmol) and K2CO3 (5.9 g, 43 mmol). The resulting mixture was stirred at 100° C. for 8 h, and allowed to cool to rt. EtOAc (300 mL) was added. The organic layer was washed with water (3×100 mL) and brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:2 v/v)). Compound 54a was obtained as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H18N2O4: 279.1 (M+H). Found 279.1.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][CH2:7][N:6]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].C(O)(C)(C)C>O>[CH2:9]([N:6]1[CH2:7][CH2:8][CH:5]1[C:3]([OH:4])=[O:2])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C1CCN1Cc1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)C1CCN1Cc1ccccc1
Reaction time: 2 h

Procedure:
N-Benzylazetidine-2-carboxylic acid methyl ester (1 g), 90 mg of t-butanol, 90 mg of water were mixed at 20 to 25° C. and 180 mg of Chirazyme L-2 were mixed and the resulting solution was heated to40° C. and stirred for 2 hours. Thereafter 1 ml of water was added thereto and washed with 4 ml of t-butyl methyl ether thrice to obtain an aqueous solution of optically active N-benzylazetidine-2-carboxylic acid. Combined organic phase gave a solution of N-Benzylazetidine-2-carboxylic acid methyl ester.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N+:34]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)([O-:36])=[O:35].O[CH2:45][CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1>C1COCC1>[N+:34]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:45][CH2:46][N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1)([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: OCCN1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
To a mixture of PPh3 (866 mg, 3.3 mmol) in THF (6 mL) is added DIAD (0.65 mL, 3.3 mmol) at 0° C. The suspension was stirred for 10 minutes, then heated to room temperature. To the mixture, 4-nitrophenol (460 mg, 3.3 mmol) and 1-(2-hydroxyethyl)-pyrrolidine (0.26 mL, 2.2 mmol) is added, and the mixture is stirred at room temperature for 16 hours, then concentrated. The residue is taken up in EtOAc, washed with 1N NaOH aqueous solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, MeOH:CH2Cl2=1:99 to 10:90) to give 277 mg of 1-[2-(4-Nitro-phenoxy)-ethyl]-pyrrolidine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([CH2:30]O)[CH2:25]1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:30][CH:26]4[CH2:27][CH2:28][CH2:29][N:24]([CH3:23])[CH2:25]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CN1CCCC(CO)C1
Agent: CCCCP(CCCC)CCCC
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CCCN(C)C1
Reaction time: 18 h
Yield: 32.5 %

Procedure:
1,1′-Azodicarbonyl)dipiperidine (560 mg, 2.2 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (240 mg, 0.75 mmol), (prepared as described for the starting material in Example 2), 1-methyl-3-piperidinemethanol (115 mg, 0.89 mmol) and tributylphosphine (440 mg, 2.2 mmol) in methylene chloride (10 ml). The mixture was stirred for 18 hours, diluted with ether and the resulting precipitate was removed by filtration. The volatiles were removed from the filtrate by evaporation, and the residue was dissolved in acetone and ethereal hydrogen chloride 1.5 ml of a 1M solution, 1.5 mmol) was added. The precipitated product was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (75/8/1). The purified solid product was triturated with ether collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinazoline (105 mg, 33%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>O>[C:13]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of piperidine-4-carboxylic acid (1.29 g, 10.0 mmol) in water was added NaOH (800 mg, 20.0 mmol). When the reaction solution was clear, (BOC)2O (2.5 g, 11.0 mmol) was added, and the reaction mixture was stirred at rt for 12 h. The solvent was removed in vacuo, and the residue was diluted with 1N HCl and EtOAc. The organic layer was extracted with EtOAc, and the organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The product was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].[CH2:17](I)[CH3:18]>CC(=O)CC.O>[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH:11]=[O:12]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOc1ccc(C=O)cc1O
Yield: 43.5 %

Procedure:
Anhydrous potassium carbonate (2.25 g, 16.3 mmol) was added to 3,4-dihydroxybenzaldehyde (1.5 g, 10.8 mmol), in butanone (30 ml), at room temperature. The reaction was stirred for 10 min after which ethyl iodide (0.872 ml, 10.8 mmol) was added dropwise and the reaction was refluxed for 3 h. The reaction mixture was diluted with water and the product was extracted with dichloromethane (3×25 ml), the combined organic layers were dried over magnesium sulphate and reduced in vacuo. Purification by column chromatography (SiO2, petroleum:ether (40:60) with an increasing gradient of ethyl acetate) afforded 0.78 g (43%) of 3-hydroxy4-ethoxybenzaldehyde as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])=[CH:17][CH:16]=2)[C@H:10]([O:35][CH2:36][C@H:37]2[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:45][C:46]1[CH:47]=[C:48]([O:56][CH3:57])[C:49]2[C:54]([CH:55]=1)=[CH:53][CH:52]=[CH:51][CH:50]=2.[N+](C1C=CC=CC=1O)([O-])=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:45][C:46]2[CH:47]=[C:48]([O:56][CH3:57])[C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:55]=2)[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])=[CH:17][CH:16]=2)[C@H:10]([O:35][CH2:36][C@H:37]2[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CCl)cc2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@@H](c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)[C@H](OC[C@H]2COC(C)(C)O2)C1
Agent: O=[N+]([O-])c1ccccc1O
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (f) the (3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was reacted with 3-chloromethyl-1-methoxy-naphthalene [example 1) (a)] to yield the (3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 773 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(O[CH:14]=[C:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[CH:14]=[N:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C:21]=1[NH2:22])=[O:17])[CH3:20]
Reactant: NNc1ccc(F)cc1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1N
Yield: 74 %

Procedure:
A stirred mixture of 11.38 g (70.0 mmole) of a commercially available sample of 4-fluorophenylhydrazine hydrochloride, 11.84 g (70.0 mmole) of ethyl (ethoxymethylene)cyanoacetate and 9.67 g (70.0 mmole) of potassium carbonate in 100 ml of ethanol was refluxed overnight and then treated with 300 ml of water. The precipitate was filtered and dried in vacuo to furnish 12.87 g (74% yield) of pale yellow crystalline solid. The sample was recrystallized from ethanol m.p. 151-2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([N:8]2[C:17](=[O:18])[CH:11]3[CH2:12][CH:13](O)[CH2:14][CH2:15][N:10]3[C:9]2=[O:19])=[N:6][CH:7]=1.C(N(S(F)(F)[F:27])CC)C.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([N:8]2[C:17](=[O:18])[CH:11]3[CH2:12][CH:13]([F:27])[CH2:14][CH2:15][N:10]3[C:9]2=[O:19])=[N:6][CH:7]=1
Reactant: O=C1C2CC(O)CCN2C(=O)N1c1ncc(Cl)cc1F
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C1C2CC(F)CCN2C(=O)N1c1ncc(Cl)cc1F
Reaction time: 1 h

Procedure:
2.6 g of 2-(5-chloro-3-fluoro-pyridin-2-yl)-7-hydroxitetrahydroimidazo-[1,5-a]-pyridin-1,3-dione (isomer B, Example H10) in 80 ml dichloromethane is treated at −55° C. to −65° C. with 1.9 ml of diethylaminosulfur trifluoride (DAST) and stirred at the same temperature for 1 hour. The reaction mixture is then allowed to stir at 20° C. over night. The resulting brownish solution is treated with ice and water and extracted with ethyl acetate. The combined extracts are washed with water, dried, filtered through a small silicagel column and evaporated to give the desired product with m.p. 154-157° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[CH2:16](O)[CH2:17][OH:18].O>C1(C)C=CC=CC=1>[C:10]1([C:5]2([C:8]#[N:9])[CH2:4][CH2:3][C:2]3([O:18][CH2:17][CH2:16][O:1]3)[CH2:7][CH2:6]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCCO
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 3 h

Procedure:
The title compound of step 2 (43.3 g, 217 mmol) and ethylene glycol (27.4 g, 435 mmol) were boiled in toluol (430 mL) with the addition of p-toluol sulphonic acid (1.87 g, 10.9 mmol) at a water separator for 3 h with reflux. After the reaction had ended, the mixture was cooled, washed with NaHCO3 solution and saturated NaCl solution, dried with Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [C:1]([OH:10])(=O)[C@H:2]([C@@H:4]([C:6](O)=[O:7])[OH:5])[OH:3].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=C(C)C=1>O>[CH2:11]([N:18]1[C:6](=[O:7])[C@@H:4]([OH:5])[C@H:2]([OH:3])[C:1]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: NCc1ccccc1
Solvent: O
Solvent: Cc1cccc(C)c1
Product: O=C1[C@@H](O)[C@H](O)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A mixture of D(-)-tartaric acid (4.5 g, 30 mmol), benzylamine (3.3 ml, 30,2 mmol) and m-xylene (50 ml) was heated at reflux temperature for 4 hours with simultaneous capture of water. The mixture was cooled to room temperature, filtered and washed with m-xylene twice (2×2 ml) and acetone (10 ml) to give (3S,4S)-1-benzyl-3,4-dihydroxy-2,5-dioxopyrrolidine (5.0 g, yield: 76%) as light yellow crystals.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([I:25])[C:21]([NH2:22])=[N:20][C:18]2=[O:19])[CH2:14][C@@H:13]1[OH:26])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:27](Br)[CH:28]=[CH2:29]>C1COCC1>[CH2:29]([O:26][C@@H:13]1[C@@H:12]([CH2:11][O:10][Si:3]([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:4])[CH3:5])[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([I:25])[C:21]([NH2:22])=[N:20][C:18]2=[O:19])[CH2:14]1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c(N)nc2=O)C[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@H]1C[C@H](n2cc(I)c(N)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of NaH (60%, 113 mg, 2.84 mmol) in THF (26 ml) under N2 atmosphere, was slowly added a solution of the starting nucleoside (39) (669 mg, 1.43 mmol) in THF (6 ml). The mixture was stirred at room temperature for 45 minutes, cooled at 0° C. and allyl bromide (134 μL, 1.58 mmol) was slowly added. After 15 h at room temperature, the solution was cooled to 0° C. and quenched by addition of H2O (5 ml). THF evaporated under reduced pressure and the product extracted into EtOAc (3×25 ml). Combined organic extracts were dried (MgSO4) filtered and the volatiles evaporated under reduced pressure to give a residue that was purified by flash chromatography on silica gel with EtOAc affording the expected 3′-O-allyl product (40) (323 mg, 44%) as a colourless oil, together with some unreacted starting material (170 mg); 1H NMR (d6 DMSO) δ 0.00 (s, 3H, CH3), 0.01 (s, 3H, CH3), 0.79 (s, 9H, 3CH3), 1.84 (ddd, J=13.3, 8.2 and 5.5 Hz, 1H, H-2′), 2.20-2.25 (m, 1H, H-2′), 3.62-3.72 (m, 2H, H-5′), 3.88-3.93 (m, 4H, H-3′,4′, HHC—CH═), 5.1 (dd, J=8.5, 1.7 Hz, 1H, CH═CHH), 5.16 (dd, J=17.2, 1.7 Hz, 1H, CH═CHH), 5.75-5.83 (m, 1H, CH═CHH), 5.94 (dd, J=8.4, 5.6 Hz, 1H, H-1′), 6.53 (br s, 1H, NHH), 7.74 (br s, 1H, NHH), 7.83 (s, 1H, H-6); MS (ES): m/z (%) (M−H) 506 (100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of pyridine-3-sulphonic acid (5.0 g), phosphorous pentachloride (8.0 g), phosphorous oxychloride (30 ml) and chloroform (30 ml) was stirred at 120° C. for 18 hours. The reaction mixture was cooled to room temperature then diluted with chloroform (30 ml) and then filtered. Hydrogen chloride gas was bubbled through the filtrate for 15 minutes and the resultant precipitate collected. This material was dried in vacuo to give the title compound as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[O:32][C:33]([CH:36]2[O:40][CH2:39][CH2:38][O:37]2)=[CH:34][CH:35]=1)CCC>CC(N(C)C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:31]4[O:32][C:33]([CH:36]5[O:40][CH2:39][CH2:38][O:37]5)=[CH:34][CH:35]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc2c(Nc3ccc(Oc4ccccc4)cc3)ccnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: c1ccc(Oc2ccc(Nc3ccnc4cc(-c5ccc(C6OCCO6)o5)ccc34)cc2)cc1
Yield: 68.1 %

Procedure:
(4-Phenoxyphenyl)-(7-iodo-quinolin-4-yl)amine (2 g) was treated with 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (2.16 g) and tetrakis (triphenylphosphine) palladium (0) (0.26 g) in dimethylacetamide (20 ml) in accordance with Procedure B. Purification via column chromatography, eluting with ethyl acetate, followed by trituration with diethylether afforded a yellow solid (1.4 g); δ H [2H6] DMSO 9.10 (1H, s), 8.45 (2H, m), 8.13 (1H, s), 7.96 (1H, d), 7.41 (4H, m), 7.22 (1H, d), 7.20-7.03 (5H, m), 6.83 (1H, d), 6.75 (1H, d), 6.02 (1H, s), 4.13 (2H, m), 4.01 (2H, m); m/z 451 (M+1)+.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8](=O)(OCC)[O:9]CC>>[OH:4][CH2:3][C:2]1([CH3:7])[CH2:5][O:6][C:8](=[O:9])[NH:1]1
Reactant: CCOC(=O)OCC
Reactant: CC(N)(CO)CO
Product: CC1(CO)COC(=O)N1
Temperature: 25 °C
Yield: 25.1 %

Procedure:
A flask with 2-amino-2-methyl-1,3-propanediol (3.32 g, 31.6 mmol) and diethyl carbonate (10 ml, 83 mmol) was fitted with a Dean-Stark trap and condenser and the suspension heated to 140° C. until 5 ml of liquid had been collected in the trap (˜8 hr). The solution was cooled to RT slowly, and the resulting white, block crystals were filtered off (2.79 g, 21.3 mmol, 67%). The supernatant was purified by flash chromatography to afford the title compound as a white solid (1.04 g, 7.94 mmol, 25%). 1H NMR (CDCl3, 400 MHz) δ 1.36 (s, 3H), 2.2 (br s, 1H), 3.56 (m, 2H), 4.06 (d, J=8.8 Hz, 1H), 4.33 (d, J=8.8 Hz, 1H), 5.2-5.3 (br s, 1H). ESI/APCI calculated for C5H9NO3: 131.06. Found: 132 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](O)[N:11]=[C:10]([CH3:15])[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O.O>C(#N)C>[Cl:18][C:12]1[CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[C:10]([CH3:15])[N:11]=1
Reactant: Cc1nc(O)cc(-c2ccc(F)cc2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: Cc1nc(Cl)cc(-c2ccc(F)cc2)n1
Reaction time: 4 h
Yield: 97 %

Procedure:
13.8 kg of 4-(4-fluorophenyl)-6-hydroxy-2-methylpyrimidine and 11.5 kg of phosphorus oxychloride were refluxed in acetonitrile, and stirred for 4 hours. The reaction solution was combined with water, and the precipitated crystal was separated, and the resultant crystal was washed and dried to obtain 14.6 kg of the target compound as a pale yellow crystal.