Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:51]([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]([C:64](=[O:88])[C@@H:65]([NH2:87])[CH2:66][CH2:67][CH2:68][O:69][Si:70]([C:83]([CH3:86])([CH3:85])[CH3:84])([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:60][CH2:59]1)=[O:57])[CH2:52][CH2:53][CH3:54]>CN(C=O)C.C(Cl)CCl>[CH2:51]([O:55][C:56]([N:58]1[CH2:59][CH2:60][N:61]([C:64](=[O:88])[C@@H:65]([NH:87][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=2)=[O:28])[CH2:66][CH2:67][CH2:68][O:69][Si:70]([C:83]([CH3:86])([CH3:85])[CH3:84])([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:62][CH2:63]1)=[O:57])[CH2:52][CH2:53][CH3:54]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: Cc1ccc2c(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)cc(C(=O)O)nc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 385 mg 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid in 10 ml DMF were added 215 mg HOBt, 270 mg EDC and 0.4 ml DIPEA. After 20 minutes 506 mg 4-[(S)-2-Amino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoyl]-piperazine-1-carboxylic acid butyl ester hydrochloride were added and the mixture stirred for 12 h. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product thus obtained was pure enough for the following transformation. Yield: 850 mg.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C@@:11]2([CH3:30])[O:29][C:14]3=[CH:15][N:16]=[C:17]([C:19]4[CH2:20][CH2:21][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH:24]=4)[CH:18]=[C:13]3[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[C:31](Cl)(=O)[CH2:32][CH2:33][CH3:34]>>[CH3:28][S:25]([N:22]1[CH2:21][CH:20]=[C:19]([C:17]2[CH:18]=[C:13]3[CH2:12][C@@:11]([CH3:30])([CH:8]4[CH2:9][CH2:10][N:5]([C:3]5[N:4]=[C:31]([CH2:32][CH2:33][CH3:34])[O:1][N:2]=5)[CH2:6][CH2:7]4)[O:29][C:14]3=[CH:15][N:16]=2)[CH2:24][CH2:23]1)(=[O:27])=[O:26]
Reactant: C[C@@]1(C2CCN(C(=N)NO)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: CCCC(=O)Cl
Product: CCCc1nc(N2CCC([C@]3(C)Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)no1

Procedure:
The title compound is prepared from (S)—N-hydroxy-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxamidine (Intermediate 43; the configuration of the stereocenter is arbitrarily assigned) and butyryl chloride following a procedure analogous to that described in Example 8. LC (method 4): tR=1.00 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:24])([S:20]([CH3:23])(=[O:22])=[O:21])[C:17](O)=[O:18])=[CH:10][CH:9]=1.C[Si](C)(C)[O:27][NH2:28].CO>ClCCl.O.CN(C=O)C>[Br:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:24])([S:20]([CH3:23])(=[O:22])=[O:21])[C:17]([NH:28][OH:27])=[O:18])=[CH:10][CH:9]=1
Reactant: CC(CCc1ccc(Br)nc1)(C(=O)O)S(C)(=O)=O
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(CCc1ccc(Br)nc1)(C(=O)NO)S(C)(=O)=O
Reaction time: 8 h
Yield: 91.6 %

Procedure:
DMF (1.6 uL, 0.02 mmol, 0.01 equiv) was added to a solution of oxalyl chloride (1.0 mL, 2.07 mmol, 1.0 equiv) and 4-(6-bromopyridin-3-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (695 mg, 2.07 mmol, 1.0 equiv) in dichloromethane (20 mL) at room temperature. After 10 min (gas evolution subsided), O-(trimethylsilyl)hydroxylamine (843 uL, 6.2 mmol, 3.0 equiv) was added and the reaction was allowed to stir overnight. Methanol (8.8 mL) was added, and the reaction was allowed stir for an additional hour. The reaction was diluted with water (80 mL), and the resulting mixture was extracted with ethyl acetate (2×65 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound as a white powder (666 mg, 92%). MS (LCMS) m/z 353.0 (M+1).
Reaction SMILES: [CH:1]([N:3]([CH2:6][CH2:7][C:8]([O:10]C)=O)[CH:4]=[O:5])=[CH2:2].[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15].C[O-].[Na+]>CO>[OH:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][OH:18])[C:8](=[O:10])[CH2:7][CH2:6][N:3]([CH:1]=[CH2:2])[CH:4]=[O:5]
Reactant: C=CN(C=O)CCC(=O)OC
Reactant: OCCNCCO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CN(C=O)CCC(=O)N(CCO)CCO
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A 50 mL single-neck round bottom flask equipped with a distillation head was charged with 15.1 grams (0.096 mole) of methyl 3-(N-vinylformamido)propionate, 9.95 grams (0.09 mole) of diethanolamine and 0.15 gram of 25% sodium methoxide in methanol solution. The mixture was stirred at 90° C. for 2 hours and the generated methanol was removed by distillation at reduced pressure. Both proton NMR and GC analyses indicated approximately a 90% conversion to the titled product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[C:8]([NH:27][C:28]1[S:29][CH:30]=[C:31]([C:33](=[N:39][OH:40])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:32]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:41][CH2:42][CH2:43]Br.C(Cl)Cl>CN(C)C=O.O>[Br:41][CH2:42][CH2:43][O:40][N:39]=[C:33]([C:31]1[N:32]=[C:28]([NH:27][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:29][CH:30]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: BrCCBr
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
4.14 g of potassium carbonate were added over 3 minutes under argon to a mixture of 4.94 g of the product of Step B in 10 ml of dimethylformamide and the mixture was stirred at 20° C. for 20 minutes. 8.65 ml of 1,2-dibromoethane were added to the mixture which was then stirred for 30 hours and poured into a mixture of 20 ml of methylene chloride and 100 ml of distilled water. The mixture was decanted and the aqueous phase was reextracted with methylene chloride. The combined organic phases were washed with distilled water, dried and vacuum filtered. The filter was rinsed and the filtrate was evaporated to dryness. The raw residue was chromatographed over silica gel and was eluted with benzene containing 5% ether. The first fraction was dissolved at 50° to 60° C. in methanol and the mixture was cooled to 0° to 5° C. and was vacuum filtered to obtain 1.16 g of the syn isomer of ethyl 2-(2-bromoethoxyimino)-2-(2-tritylamino-4-thiazolyl)-acetate in the form of cream-white crystals melting at 117° C. and a second homogenous fraction of 1.258 g of the said product was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[NH2:12][OH:13].Cl.C([O-])(O)=O.[Na+]>CCO>[OH:13][NH:12][C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=[NH:2]
Reactant: NO
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1ccc2[nH]ccc2c1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-cyanoindole (5.00 g), NH2OH.HCl (6.11 g) and NaHCO3 (14.77 g) in EtOH (176 ml) was heated at 70° C. under an atmosphere of Ar overnight and then at 80° C. for 2.5 hours. The reaction mixture was then filtered and evaporated to give a yellow-orange solid (crude material D1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:10]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1)=[CH2:11]
Reactant: OCc1cc(Br)ccn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1ccnc(CO)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride (94 mg, 0.134 mmol) was added to a degassed solution of (4-bromo-pyridin-2-yl)-methanol (252 mg, 1.34 mmol) and tributyl(vinyl)tin (0.588 mL, 2.01 mmol) in toluene (10 mL) under nitrogen and the reaction mixture was stirred at 50° C. for 18 hours. Additional tributyl(vinyl)tin (0.176 mL, 0.67 mmol) and bis(triphenylphosphine)palladium(II) dichloride (47 mg, 0.067 mmol) were added and stirring was continued for 18 hours at 80° C. under nitrogen. The reaction mixture was cooled to room temperature and silica gel was added. The solvent was evaporated and the residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:2 to 1:4 to afford the title compound (282 mg, 1.34 mmol) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ3.60-3.80 (br s, 1H), 4.78 (s, 2H), 5.52 (d, J=10.9 Hz, 1H), 6.01 (d, J=17.6 Hz, 1H), 6.69 (dd, J=17.6, 10.9 Hz, 1H), 7.22 (d, J=5.4 Hz, 1H), 7.27 (s, 1H), 8.52 (d, J=5.4 Hz, 1H).
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)=O.[CH2:14](N(C)C)C1C=CC=CC=1.C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCC>[CH:2]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)=[CH2:14]
Reactant: N#CC=Cc1ccc(C(=O)Cl)cc1
Reactant: CN(C)Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: C=Cc1ccc(C=CC#N)cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
2.39 g (12.5 mmols) of 4-chloroformylcinnamonitrile, 1.69 g (12.5 mmols) of N-benzyldimethylamine and 0.0280 g (0.125 mmol) of palladium acetate are added under argon to 25 ml of toluene. The reaction mixture is stirred for 4 hours at 140° C. under an ethylene pressure of 10 bar. The mixture is then extracted by shaking at room temperature with 100 ml of 2N HCl and 100 ml of 2N NaOH and is dried over magnesium sulfate. The solution is then evaporated and the residue is chromatographed over silica gel using methylene dichloride as the migrating agent. The yellow oil thus obtained is dissolved in boiling n-pentane. 0.84 g (44% of theory) of 4-vinylcinnamonitrile are formed at -20° C. in the form of white crystals; melting point 45.8° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[Cl:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl>>[Cl:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: ClCCOCCCl
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: N#Cc1ccnc(-c2cn(CCOCCCl)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and bis(2-chloroethyl)ether according to the procedure for the preparation of Example 43, part A. [M+H] Calc'd for C13H13ClN4O, 278. Found, 277, 279.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[CH:9](/B(O)O)=[CH:10]/[CH3:11].C(C1OC(C=O)=CC=1)C1C=CC=CC=1>CN(C=O)C>[CH:9](/[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1)=[CH:10]/[CH3:11]
Reactant: O=Cc1cc(Br)co1
Reactant: C/C=C\B(O)O
Agent: O=Cc1ccc(Cc2ccccc2)o1
Solvent: CN(C)C=O
Product: C/C=C\c1coc(C=O)c1
Yield: 48.2 %

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carboxaldehyde (1.1 g, 6.3 mmol, 1 equiv) and cis-propene boronic acid (0.65 g, 7.5 mmol, 1.2 equiv) using the conditions to synthesize 5-benzyl-furan-2-carbaldehyde, with the exception that the reaction was run in DMF (20 mL). The resulting residue was purified via ISCO Companion (0-25% EtOAc/heptane over 30 min, retention time of product: 23-26 min) to give (Z)-4-(prop-1-enyl)furan-2-carbaldehyde (0.4130 g, 48% yield). LC/MS m/e 136.8 (M+H). 1H NMR (400 MHz, CD3CN) δ (ppm): 9.59 (d, J=0.63 Hz, 1 H), 7.83 (s, 1 H), 7.42 (s, 1 H), 6.23 (dd, J=11.40, 1.68 Hz, 1 H), 5.79-5.89 (m, 1 H), 1.87 (dd, J=7.10, 1.78 Hz, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]=[N:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[CH:27]([CH3:29])[CH3:28])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[BH4-].[Na+].O.C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:9][C:4]1[CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][NH:17][C:18]2[C:23]([CH:24]([CH3:25])[CH3:26])=[CH:22][CH:21]=[CH:20][C:19]=2[CH:27]([CH3:29])[CH3:28])[C:2]([CH3:1])=[C:6]([CH3:7])[C:5]=1[CH3:8]
Reactant: CC1=C(C)C(c2ccccc2C=Nc2c(C(C)C)cccc2C(C)C)C(C)=C1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(C)C(c2ccccc2CNc2c(C(C)C)cccc2C(C)C)C(C)=C1C
Yield: 82.3 %

Procedure:
To a solution of N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethylene]-N-(2,6-diisopropylphenyl)amine (10.0 mmol) in acetic acid (7.0 mL) was added sodium borohydride (13.0 mmol). The mixture was reacted at room temperature for 1 hr. Water and toluene were then added to the reaction mixture. The organic layer was dried and concentrated. The obtained oily substance was purified by silica gel column chromatography to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethyl]-N-(2,6-diisopropylphenyl)amine (3.19 g, yield 82.4%) as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[C:13](=[C:15]([O:22][CH3:23])[CH:16]=[CH:17][C:18]=3[C:19]([OH:21])=[O:20])[O:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[C:13](=[C:15]([O:22][CH3:23])[CH:16]=[CH:17][C:18]=3[C:19]([O:21][C:30]3[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=3)=[O:20])[O:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)O)c23)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c23)C1

Procedure:
A solution of 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylic acid (from step 7) (0.352 g, 1.1 mmol), 4-nitrophenol (0.229 g, 1.65 mmol), EDCI (0.253 g, 1.32 mmol) and 4-(N,N-dimethyl)aminopyridine (0.027 g, 0.22 mmol) in tetrahydrofuran was stirred overnight. Water was added to RM, extracted with ethyl acetate and org layer was concentrated after drying on anhy. Sod. Sulphate. The solid was chromatographed on silica gel to yield 4-nitrophenyl 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylate.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Nc1ncccn1
Reactant: O=CC(CO)OC(C=O)n1ccc(=O)[nH]c1=O
Solvent: O
Product: O=c1ccn([C@@H]2O[C@H](CO)C(O)N(c3ncccn3)C2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde, (uridinedialdehyde), (6.05 g) was dissolved in water (25 ml). To the solution was added 2-aminopyrimidine (2.38 g). The mixture was stirred at ambient temperature for eight hours to give a clear solution. The solution was lyophilized to give white powder of 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]uracil (8.40 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][C@@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)=[CH:17][C:16]=2[CH3:28])=[CH:11][C:10]=1[CH2:29][O:30][C:31]1[CH:43]=[CH:42][C:34]2[C@H:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:36][O:37][C:33]=2[CH:32]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][C@@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)=[CH:17][C:16]=2[CH3:28])=[CH:11][C:10]=1[CH2:29][O:30][C:31]1[CH:43]=[CH:42][C:34]2[C@H:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:36][O:37][C:33]=2[CH:32]=1
Reactant: Cc1cc(O[C@@H]2CCOC2)cc(C)c1-c1ccc(OCc2ccccc2)c(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(O[C@@H]2CCOC2)cc(C)c1-c1ccc(O)c(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 12 h
Yield: 14.1 %

Procedure:
2-((S)-6-((4-(Benzyloxy)-2′,6′-dimethyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 36c (152 mg, 0.26 mmol) was dissolved in 5 mL of ethyl acetate, followed by addition of Pd/C (30 mg, 10%). The reaction solution was stirred for 12 hours. The resulting solution was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by TLC with elution system A to obtain the crude title compound 2-((S)-6-((4-hydroxy-2′,6′-dimethyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 36 (18 mg, yield 14.1%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]([OH:22])[CH2:20][O:21][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(O)Cc1ccc2c(c1OCc1ccccc1)CCC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(O)Cc1ccc2c(c1OCc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of (±)-3-[4-(benzyloxy)-2,3-dihydro-1H-inden-5-yl]propane-1,2-diol (9.10 g, 30.5 mmol) in N,N-dimethylformamide (150 mL) was added tert-butyldimethylsilyl chloride (4.83 g, 32.04 mmol) followed by imidazole (2.49 g, 36.60 mmol) and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was quenched with methanol (5 mL) and diluted with diethyl ether (500 mL). The organic layer was washed with aqueous hydrogen chloride (200 mL, 0.5 N), water (3×200 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4) gave 9.20 g (73%) of (±)-1-[4-(benzyloxy)-2,3-dihydro-1H-inden-5-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol as a colorless oil. Rf=0.37 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C25H36O3Si: C, 72.77; H, 8.79. Found: C, 72.3; H, 8.48.
Reaction SMILES: CC(P(C(C)(C)C)[C:6]1[C:11]([C:12]2C=CC=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.[C:22]1([C:28]#[C:29][P:30](=[O:35])([OH:34])[O:31][CH2:32][CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(C1C=CC=CC=1)C#C>[Au].ClC(Cl)C>[CH2:32]([O:31][P:30]1(=[O:34])[CH:29]=[C:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:14]=[C:13]([CH2:12][C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:35]1)[CH3:33]
Reactant: CCOP(=O)(O)C#Cc1ccccc1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: [Au]
Agent: C#CCc1ccccc1
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccccc2)C=C(Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
Method 2—A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen phenylethynylphosphonate (63.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, prop-2-ynylbenzene (70 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-phenyl-6-benzyl-1,2-oxaphosphorin 2-oxide (68.5 mg, 70%) which is a title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[N+:27]([O-])([O-:29])=[O:28].[K+]>ClCCCl>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([N+:27]([O-:29])=[O:28])=[C:7]([CH:6]=1)[C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cccc(Oc2cc(C(F)(F)F)ccc2Cl)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCCl
Product: O=C(O)c1cc(Oc2cc(C(F)(F)F)ccc2Cl)ccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
The acid from (b) (2.0 g) was added to a mixture of concentrated sulphuric acid (15 ml) and 1,2-dichloroethane (10 ml) kept at 0°. Potassium nitrate (1.2 g) was then added in portions with stirring over a period of 30 minutes, keeping the temperature at 0°. The mixture was stirred for a further hour at 0° and then for 3 hours at room temperature. The mixture was then poured on to ice and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to give a dark gum. This was extracted several times with boiling cyclohexane. The residue crystallised on cooling and was identified as the required nitro-acid, with a melting point of 147°-148°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](N)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:21].[Na+].[OH-].[Na+]>O>[I:21][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[CH:4]2
Reactant: [I-]
Reactant: Cn1ncc2cc(N)ccc21
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cn1ncc2cc(I)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.1 %

Procedure:
To 1-Methyl-1H-indazol-5-amine (500 mg, 3.40 mmol) in a mixture of concentrated sulfuric acid (1.3 ml) and water (5.5 ml) cooled down to 0° C., was added dropwise a solution of sodium nitrite (258 mg, 3.74 mmol) in water (0.5 ml). The reaction mixture was stirred at 0° C. for 10 minutes then added dropwise to a solution of sodium iodide (1.5 g) in water (4.5 ml) cooled to 0° C. After complete addition, the reaction mixture was heated to 90° C. for an additional 20 minutes. The resultant mixture was basified with a diluted solution of sodium hydroxide and extracted with ethylacetate. The organic phase was washed further with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography eluting with 20% EtOAc in petroleum ether to afford the title compound (475 mg, 54% yield). 1H NMR (DMSO D6, 400 MHz) 4.03 (3H, s), 7.52 (1H, d), 7.63 (1H, dd), 7.99 (1H, s), 8.17 (1H, s).