Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:18])[C:5]([C:16]#[N:17])=[C:6]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8](=[O:15])[C:7]=12.S(=O)(=O)(O)[OH:20]>O>[CH3:1][C:2]1[NH:3][C:4](=[O:18])[C:5]([C:16]([NH2:17])=[O:20])=[C:6]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8](=[O:15])[C:7]=12
Reactant: Cc1[nH]c(=O)c(C#N)c2c1C(=O)c1ccccc1-2
Reactant: O=S(=O)(O)O
Solvent: O
Product: Cc1[nH]c(=O)c(C(N)=O)c2c1C(=O)c1ccccc1-2

Procedure:
A mixture of approximately 2 parts of 3,9-dihydro-1-methyl-3,9-dioxo-2H-indeno[2,1-c]pyridine-4-carbonitrile, 37 parts of concentrated sulfuric acid, and 1 part of water is heated at 90°-95° for 2 hours, then slowly diluted with 175 parts of water. The precipitate which forms is filtered off, washed with methanol, dried in vacuo, and crystallized from aqueous N,N-dimethylformamide to give 3,9-dihydro-1-methyl-3,9-dioxo-2H-indeno[2,1-c]pyridine-4-carboxamide as a pale yellow solid melting above 300°. The product has the formula ##STR17##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([NH2:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C.Cl>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH:4]([NH:12][C:17]1[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCC(N)C(=O)OC
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCCCCC(Nc1cc(F)cc(C(F)(F)F)c1)C(=O)OC
Reaction time: 0.08 h
Yield: 206.9 %

Procedure:
Reaction performed in parallel in 8×50 mL reaction flasks. Copper (II) acetate (270 mg, 1.48 mmol., 1.1 eq.) and 4 Å molecular sieves (700 mg) were charged in 50 mL round bottom flask. Dichloromethane (10 mL, previously saturated with air) was added a single portion. 2-amino-non-8-enoic acid methyl ester (250 mg, 1.35 mmol., 1.0 eq.) was added and the reaction mixture was stirred for a further 5 min by when the initial light blue solution had turned dark blue. 3-fluoro-5-trifluoromethylbenzene boronic acid (560 mg, 2.70 mmol., 2 eq.) was added followed by triethylamine (218 mg, 2.70 mmol., 2 eq.). The reaction mixture was stirred over night under an air atmosphere. The 8 reaction mixtures were combined together and 1M hydrochloric acid (150 mL) was added. The mixture was stirred for a further 5 min until the aqueous layer turned pale blue and the organic layer turned pale yellow. The organic layer was collected, dried over sodium sulfate and the solvent removed under vacuum. The residue was purified by flash column chromatography, using a dichloromethane:heptanes gradient (from neat heptane to 50% dichloromethane in heptanes). After combining the relevant fractions and solvent removal, 970 mg (26%) of the title compound was isolated as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 6.66 (d, J=8.54 Hz, 1 H), 6.61 (s, 1 H), 6.42 (d, J=10.83 Hz, 1 H), 5.72-5.87 (m, J=6.71, 6.71, 10.26, 17.05 Hz, 1 H), 5.00 (dd, J=1.83, 17.09 Hz, 1 H), 4.95 (dt, J=0.95, 10.15 Hz, 1 H), 4.48 (d, J=8.54 Hz, 1 H), 4.05 (dt, J=6.45, 8.32 Hz, 1 H), 3.76 (s, 3H), 2.05 (q, J=6.92 Hz, 2 H), 1.82-1.93 (m, 1 H), 1.71-1.82 (m, 1 H), 1.30-1.45 (m, 6 H). LC-MS: purity 94% (UV), tR 2.63 min, m/z [M+H]+ 348.00.
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(OS(C(F)(F)F)(=O)=O)C=C2)(=[O:6])C(C)(C)C.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:57]=[CH:56][C:55]3[C:50](=[CH:51][C:52]([CH3:73])=[C:53]([C@H:65]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])[CH2:66][OH:67])[C:54]=3[C:58]3[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=3)[N:49]=2)=[CH:44][CH:43]=1.C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(CC)C=C2)CO)(C)(C)C>>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]2[CH:57]=[CH:56][C:55]3[C:50](=[CH:51][C:52]([CH3:73])=[C:53]([C@H:65]([O:68][C:69]([CH3:70])([CH3:72])[CH3:71])[C:66]([OH:6])=[O:67])[C:54]=3[C:58]3[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=3)[N:49]=2)=[CH:46][CH:47]=1
Reactant: Cc1cc2nc(-c3ccc(Cl)cc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: CCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Product: Cc1cc2nc(-c3ccc(Cl)cc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-(2,5-Bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic acid was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)acetic acid (compound of Example 26), except that (S)-2-(2,5-bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyethanol was used instead (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)ethanol. 1H-NMR 300 MHz, (CD3OD) δ 8.15-8.02 (m, 4H), 7.98 (d, 1H), 7.70-7.60 (m, 5H), 7.38 (d, 1H), 5.24 (s, 1H), 2.74 (s, 3H), 0.98 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C28H25Cl2NO3: 495.4. Found: 494.2, 496.2, 498.2.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[CH:30]=2)=[CH:11][C:12]2[CH:17]=[N:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[N:14][C:13]=2[N:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](Cl)(=[O:42])[CH:40]=[CH2:41].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([NH:5][C:6](=[O:7])[NH:8][C:9]1[C:10]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[CH:30]=2)=[CH:11][C:12]2[CH:17]=[N:16][C:15]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])[C:39](=[O:42])[CH:40]=[CH2:41])=[N:14][C:13]=2[N:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)CCCCNc1ncc2cc(-c3cc(OC)cc(OC)c3)c(NC(=O)NC(C)(C)C)nc2n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N(CCCCN(CC)CC)c1ncc2cc(-c3cc(OC)cc(OC)c3)c(NC(=O)NC(C)(C)C)nc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material 1-(tert-butyl)-3-(2-((4-(diethylamino)butyl)amino)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea (PD173074) can be purchased from, e.g., SelleckChem.com. In a dried vessel, acryloyl chloride (2 equiv.) and diisopropylethylamine (4.3 equiv.) are added to a solution of 1-(tert-butyl)-3-(2-((4-(diethylamino)butyl)amino)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea (1 equiv.) in anhydrous dichloromethane at 0° C. After stirring at room temperature for 2 hours, the reaction mixture is concentrated, diluted with DMSO and purified by reverse phase HPLC (5-95% water/acetonitrile). After concentrating the fractions, the product N-(7-(3-(tert-butyl)ureido)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-2-yl)-N-(4-(diethylamino)butyl)acrylamide is obtained as a pale yellow foam. LCMS (M+1)=578.2.
Reaction SMILES: C([O:3][C:4]([NH:6][C:7]1([C:16]([OH:18])=[O:17])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=[O:5])C>S(Cl)(Cl)=O>[C:4]([NH:6][C:7]1([C:16]([O:18][C:16]([C:7]2([NH:6][C:4]([OH:5])=[O:3])[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)=[O:17])=[O:17])[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15]1)([OH:3])=[O:5]
Reactant: CCOC(=O)NC1(C(=O)O)Cc2ccccc2C1
Solvent: O=S(Cl)Cl
Product: O=C(O)NC1(C(=O)OC(=O)C2(NC(=O)O)Cc3ccccc3C2)Cc2ccccc2C1
Yield: 56.3 %

Procedure:
The resultant compound of Example 4 (500 mg, 2.00 mmol) was dissolved in thionyl chloride (3 ml). Evaporation after 17 hours provided a solid which was recrystallized from ethyl acetate/hexane to give 239 mg (59%) of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11](O)=[O:12])=[C:8]([CH3:14])[C:7]=2[CH:15]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[H-].C(O[Al](OCC(C)C)OCC(C)C)C(C)C.[Li+].Cl>O1CCCC1.CN(C)C=O.[O-2].[O-2].[Mn+4]>[CH:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:15][C:7]=2[C:8]=1[CH3:14])=[O:12]
Reactant: Cc1c(C(=O)O)oc2ccc(C#N)cc12
Agent: [Mn+4]
Agent: CC(C)CO[Al](OCC(C)C)OCC(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(C=O)oc2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.7 %

Procedure:
To 5-cyano-3-methyl-1-benzofuran-2-carboxylic acid (2.58 g) synthesized above in tetrahydrofuran (30 mL) were added oxalyl chloride (1.32 mL) and several drops of N,N-dimethylformamide, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give a pale-brown solid. To a solution (50 mL) of the obtained solid in tetrahydrofuran was added a 1.1M solution (12.0 mL) of lithium tri(isobutoxy)aluminum hydride in tetrahydrofuran at −78° C., and the mixture was stirred at −78° C. for 1.5 hr then at 0° C. for 3 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a pale-brown solid. To a solution (40 mL) of the obtained solid in tetrahydrofuran was added active manganese dioxide (10.0 g), and the mixture was stirred at 50° C. overnight. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (1.49 g, 63%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[C:13]([CH:19]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[C:10]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:11][CH:12]=[C:13]([CH:19]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(Cl)c(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of ethyl 5-(benzyloxy)-6-chloronicotinate (2.1 g, 0.00719 mol) in THF (21 mL) in a 250 mL sealed tube, were added Pd2(dba)3 (395 mg, 0.00043 mol, Aldrich), NH2Boc (1.68 g, 0.0143 mol, Aldrich), X-phos (500 mg, 0.0010 mol, Aldrich) and K3PO4 (4.5 g, 0.0010 mol). The vessel was purged with argon gas for 10 min. The reaction mixture was then stirred for 12 h at 80° C. After completion of the reaction (monitored by TLC, 30% EtOAc in hexane), the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, and purified by column chromatography, silica gel (60-120 mesh) using 23-30% EtOAc in petroleum ether as the eluent to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.22 (s, 1H), 8.46 (d, J=1.8 Hz, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.53 (d, J=6.6 Hz, 2H) 7.42-7.33 (m, 3H), 5.22 (s, 2H), 4.36 (q, J=6.9 Hz, 2H), 1.44 (s, 9H), 1.36 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1)[CH:6]=O.[C:17]([O:21][C:22](=[O:42])[CH:23](P(OCC)(OCC)=O)[CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])([CH3:20])([CH3:19])[CH3:18].O.[OH-].[Li+].O>C1COCC1.C(O)C.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:42])/[C:23](=[CH:6]/[C:5]1[CH:8]=[CH:9][C:10]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])([CH3:18])([CH3:20])[CH3:19]
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(/C=C(\CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (295 mg) obtained in Example 1 in THF (5.0 mL) and ethanol (5.0 mL), 4-(tert-butyldimethylsilanyloxy)-2-(diethoxyphosphoryl)butyric acid tert-butyl ester (509 mg) and lithium hydroxide monohydrate (104 mg) were added one by one, and the reaction solution was agitated at room temperature overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (heptane-ethyl acetate=2:1->1:1), and 395 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [N:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8]P(=C(C[N+](C)(C)C)O)=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].NC1C=CC(C[OH:26])=CC=1.Cl.[N+]([O-])([O-])=O.[Na+].[N-]=[N+]=[N-].[Na+]>>[N:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][OH:26])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: C[N+](C)(C)CC(O)=[P+]([O-])Cc1ccc(N=[N+]=[N-])cc1
Reactant: Nc1ccc(CO)cc1
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [N-]=[N+]=[N-]
Product: [N-]=[N+]=Nc1ccc(CO)cc1
Yield: 55 %

Procedure:
For example, 4-azidobenzylphosphorylcholine was made as follows: 4-aminobenzyl alcohol was treated with HCl and reacted with sodium nitrate, followed by sodium azide to yield 4-azidobenzyl alcohol. The product was recovered in 55% yield as a brown solid and purified by column chromatography. The product was characterized by NMR and IR. 4-azidobenzyl alcohol was treated with triethylamine, and 2-chloro-2-oxo-1,3,2-dioxaphospholane (COP) was added to the solution. The resulting compound was reacted with trimethylamine to yield the final product of 4-azidobenzylphosphorylcholine. The final product was obtained as a pale brown powder in 60% yield and characterized by NMR and IR.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@H:27]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([CH3:39])[CH2:28]1)(C(C)(C)C)(C)C.CCCCCCC>C1COCC1>[OH:26][CH:27]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([CH3:39])[CH2:28]1
Reactant: C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: C[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF, 28 mL) was added to a solution of (2R,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-1-carboxylate (3.87 g, 12.27 mmol) in THF (10 mL). The reaction mixture was stirred at ambient temperature for about 3 hours. The solvent was removed in vacuo and the residue partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (3×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel flash chromatography eluting with 40% EtOAc:heptane yielded (2R)-tert-butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate (2.3 g, 11.4 mmol) as a colorless oil. 1H NMR (d6 DMSO, 400 MHz) 4.41 (1H, br), 4.00 (1H, br), 3.48 (2H, br), 2.3-2.0 (2H, m), 1.72 (1H, m), 1.46 (9H, s) and 1.22 (3H, d).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22]I>C1COCC1.CCCCCC>[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][N:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(C#N)cc1
Reactant: ClCCCCI
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)N(CCCCCl)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9 g (54.1 mmol) of N-(4-cyanophenyl)acetamide are dissolved in 100 ml of THF. The mixture is cooled to 0° C. before the dropwise addition of 51 ml of a 1.6 N solution in hexane of nBuLi (1.5 eq.). The solution is left for one hour to return to ambient temperature and is then cooled to 0° C. before the dropwise addition of 9.9 ml of 1-chloro-4-iodobutane (81 mmol). The reaction mixture is stirred at ambient temperature for 18 h and then hydrolysed with a saturated aqueous solution of ammonium chloride (100 ml) and extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated. Purification by chromatography on silica (eluant: petroleum ether/ethyl acetate: 1/1) yields a yellow oil containing the expected product.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([O:21][C:20]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18](=[O:28])[CH2:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[CH3:31])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+]>CO>[OH:28][CH:18]1[CH2:17][C:14]2([CH2:13][CH2:12][N:11]([C:9]([C:8]3[CH:29]=[CH:30][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH3:31])[CH:7]=3)=[O:10])[CH2:16][CH2:15]2)[O:21][C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:19]1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CC(=O)C=C(c2cccnc2)O3)ccc1OC(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(C(=O)N2CCC3(CC2)CC(O)C=C(c2cccnc2)O3)ccc1OC(C)C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 3-(4-isopropoxy-3-methyl-benzoyl)-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (3.65 g, 8.68 mmol) in methanol (35 mL) was slowly added sodium borohydride (328 mg, 8.68 mmol). After 2 hours, saturated ammonium chloride (75 mL) was added. The mixture was allowed to stir for 15 minutes, and the mixture was concentrated to half volume under reduced pressure. The remaining suspension was extracted with ethyl acetate (3×75 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (70-100% ethyl acetate/hexane) to afford (4-hydroxy-2-(pyridin-3-yl)-1-oxa-9-azaspiro[5.5]undec-2-en-9-yl)(4-isopropoxy-3-methylphenyl)methanone (3.32 g). 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J=1.8 Hz, 1H), 8.57 (dd, J=4.7, 1.3 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.31 (dd, J=8.0, 4.8 Hz, 1H), 7.23 (dd, J=13.9, 5.8 Hz, 2H), 6.81 (d, J=8.1 Hz, 1H), 5.56 (d, J=3.5 Hz, 1H), 4.56 (dt, J=12.0, 6.0 Hz, 2H), 4.51-4.22 (m, 1H), 3.82 (br s, 1H), 3.39 (br s, 2H), 2.21 (s, 3H), 2.17-1.55 (m, 6H), 1.34 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 422.2, found 423 (M+1)+; Retention time: 1.23 minutes (3 min run).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C(CC)C.[CH3:41][S:42][C:43]1[N:48]=[C:47]([CH:49]=[O:50])[CH:46]=[CH:45][N:44]=1>C(OC)(C)(C)C>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([CH:49]([C:47]2[CH:46]=[CH:45][N:44]=[C:43]([S:42][CH3:41])[N:48]=2)[OH:50])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@@H](C)O1
Reactant: CSc1nccc(C=O)n1
Agent: [Li]C(C)CC
Solvent: COC(C)(C)C
Product: CSc1nccc(C(O)c2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@H](C)C3)c(F)c2F)n1
Reaction time: 0.33 h
Yield: 34.5 %

Procedure:
Starting materials: (2R,6R)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 43, 7.36 g, 14.84 mmol) in t-BuOMe (20 mL) was added s-BuLi (12.45 mL, 16.19 mmol) at −75° C. under nitrogen atmosphere. After stirring for 20 minutes at this temperature, it was then transferred via cannula to a solution of 2-(methylthio)pyrimidine-4-carbaldehyde (2.08 g, 13.49 mmol) in t-BuOMe (20 mL) (precooled down to −70° C.), the mixture was then stirred for 0.5 hour at −70° C., quenched with saturated aqueouse ammonium chloride solution and extracted with ethylacetate, dried and concentrated, purified by flash column chromatography on silica gel with Hex/EtOAc to give the desired product (3.024 g).
Reaction SMILES: [Cl:1][C:2]1[S:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([C:11]#[N:12])=[C:9]([OH:10])[C:4]=2[C:3]=1[C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21]([OH:23])=O)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:51][CH2:52][CH2:53][CH2:54][OH:55]>>[Cl:1][C:2]1[S:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([C:11]#[N:12])=[C:9]([OH:10])[C:4]=2[C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]([NH:51][CH2:52][CH2:53][CH2:54][OH:55])=[O:23])=[CH:24][CH:25]=1
Reactant: NCCCO
Reactant: N#Cc1c(O)c2c(-c3ccc(OCC(=O)O)cc3)c(Cl)sc2[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: N#Cc1c(O)c2c(-c3ccc(OCC(=O)NCCCO)cc3)c(Cl)sc2[nH]c1=O
Reaction time: 18 h

Procedure:
A suspension of 2-[4-(2-chloro-5-cyano-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridin-3-yl)phenoxy]acetic acid (35 mg, 0.093 mmol), HOBt (13 mg, 0.093 mmol), PS-DCC (88 m, 0.121 mmol, 1.37 mmol/g loading), and 3-amino-propan-1-ol (7 mg, 0.0098 mmol) were shaken in a vial at 50 C for 18 h. The reaction was then filtered through celite, eluting with MeOH, and the eluent was concentrated under reduced pressure. The residue was purified by RP-HPLC to give the title compound. MS (ESI) m/e 432 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60 (m, 2H), 3.21 (m, 2H), 3.42 (t, J=6.27 Hz, 2H), 4.49 (s, 2H), 6.95 (d, J=8.81 Hz, 2H), 7.23 (d, J=8.81 Hz, 2H), 8.11 (m, 1H).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:9]=[C:8]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[Cl:23][CH2:24][C:25]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[CH:9]=[C:8]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[N:7]=[C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:11]=2)[CH2:13][CH2:14]1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCNCC1
Solvent: ClC(Cl)Cl
Product: O=C(CCl)N1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Yield: 97 %

Procedure:
The starting 1-(2-chloroacetyl)-4-[2,6-di(1-pyrrolidinyl)-4-pyrimidinyl]piperazine was prepared as follows: 1-[2,6-di(1-pyrrolidinyl)-4-pyrimidinyl]piperazine (1.65 g, 5.4 mmol) was dissolved in anhydrous chloroform (30 ml), the solution was cooled to 0°-5° C. and 2-chloroacetyl chloride (0.50 ml, 0.79 g, 7.0 mmol) in anhydrous chloroform (5 ml) was added dropwise under stirring. The mixture was stirred for one hour, concentrated and the residue was dissolved in 100 ml of water. The aqueous solution was made alkaline with conc. NH4OH and stirred for one hour. During this period the separated oil solidified. The solids were collected, washed with icecold water until neutral and dried. In this manner 2.0 g of the desired chloroacetyl compound was obtained, yield: 97.0% mp. 153°-156° C.