Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[C:5]([CH3:14])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)[N:3]=1.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([CH3:14])[N:4]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)[N:3]=1
Reactant: CCOC(=O)CCc1c(C)nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of ethyl 3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (760 mg), 1 N aqueous sodium hydroxide solution (5 ml), ethanol (5 ml), and tetrahydrofuran (5 ml) was stirred at room temperature for two hours. The reaction mixture was poured into water, which was acidified with 1 N hydrochloric acid, and precipitated crystals were collected by filtration. This was recrystallized from methanol-ethyl acetate, and 3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid was obtained (550 mg, yield: 77%). Melting point: 170–171° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[CH:43][C:38]3[NH:39][C:40](=[O:42])[NH:41][C:37]=3[CH:36]=2)O1.[CH3:46]S(C)=O>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>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[C:10]([CH3:46])=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:44]=[CH:43][C:38]3[NH:39][C:40](=[O:42])[NH:41][C:37]=3[CH:36]=2)[CH:3]=1)=[O:15]
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CS(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4[nH]c(=O)[nH]c4c3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one (61.0 mg, 0.235 mmol), DMSO (1.5 mL) sodium carbonate (0.281 mL, 0.562 mmol), and bis(triphenylphosphine)palladium(II) chloride (10.13 mg, 0.014 mmol). The final product was collected as 19 mg (21%). LCMS E-S (M+H)=486.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.8 Hz, 6H), 2.12 (s, 3H), 2.24 (s, 3H), 2.43 (s, 3H), 4.39 (d, J=4.6 Hz, 2H), 5.15-5.35 (m, 1H), 5.89 (s, 1H), 7.05 (d, J=8.1 Hz, 1H), 7.61 (s, 1H), 7.77-7.93 (m, 2H), 8.70-8.85 (m, 1H), 10.79 (br. s., 1H), 10.87 (br. s., 1H), 11.54 (br. s., 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#N)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:13].[Na+].Cl.C([OH:18])C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:18])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCO
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Agent: Cl
Agent: [Na+]
Product: O=C(O)C1(c2ccc(Br)cc2)CC1
Temperature: 100 °C

Procedure:
To a room temperature solution of 1-(4-bromophenyl)cyclopropanecarbonitrile from Step 1 (13 g) in ethyl alcohol (110 mL) was added a solution of 56 mL of sodium hydroxide (25% NaOH in water W/W). The mixture was heated at 100° C. overnight. It was cooled to room temperature and poured into ice and hydrogen chloride (1 N), and extracted with dichloromethane (2×100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo to yield the title compound.
Reaction SMILES: O[C:2](C(F)(F)F)=O.[CH3:8][C:9]([CH3:36])([CH3:35])[C:10]#[C:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[C:14]([N:20]([C@@H:30]([CH3:34])[CH2:31][CH2:32]O)[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:56]1(=[O:66])[NH:60][C:59](=[O:61])[C:58]2=[CH:62][CH:63]=[CH:64][CH:65]=[C:57]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:2][O:19][C:17]([C:15]1[S:16][C:12]([C:11]#[C:10][C:9]([CH3:36])([CH3:35])[CH3:8])=[CH:13][C:14]=1[N:20]([C@@H:30]([CH3:34])[CH2:31][CH2:32][N:60]1[C:56](=[O:66])[C:57]2[C:58](=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:59]1=[O:61])[C:21]([C@H:23]1[CH2:24][CH2:25][C@H:26]([CH3:29])[CH2:27][CH2:28]1)=[O:22])=[O:18]
Reactant: C[C@@H](CCO)N(c1cc(C#CC(C)(C)C)sc1C(=O)O)C(=O)[C@H]1CC[C@H](C)CC1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@@H](C)CCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 5-(3,3-dimethyl-but-1-ynyl)-3-[(3-hydroxy-1-(S)-methyl-propyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid TFA salt (1.40 g, 3.23 mmol) in THF (30 mL) was cooled to 0° C. and triphenylphosphine (2.53 g, 9.69 mmol) was added followed by phthalimide (0.713 g, 4.84 mmol). The reaction was stirred until homogenious then DIAD (1.06 mL, 5.49 mmol) was added. After warming to rt., the reaction was determined to be complete by LC/MS in 1 h. The reaction was quenched with CH3OH (1.0 mL) and the solvent removed under reduced pressure. 5-(3,3-Dimethyl-but-1-ynyl)-3-[[3-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-1-(S)-methyl propyl]-(trans-4-methyl-cyclohexylcarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (1.67 g, 92%) was isolated by silica gel chromatography as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:18][N:19]([CH3:27])[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:18][N:19]([CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]3[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)[CH2:23][CH2:22]1)[CH3:27]
Reactant: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Reactant: CN(C)CC1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cn(C(C)C)c2cc(N3CCC(CN(C)C)CC3)cc(C(=O)O)c12
Temperature: 98 °C
Yield: 53.8 %

Procedure:
To a 10-mL microwave tube were added 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (100 mg, 0.338 mmol),1,4-dioxane (2 mL), N,N-dimethyl-1-(4-piperidinyl)methanamine (52.8 mg, 0.371 mmol) and sodium tert-butoxide (71.4 mg, 0.743 mmol), and the mixture was degassed for 5 min. Choro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]Pd(11)Me-t-butylether adduct (13.96 mg, 0.017 mmol) was added and the tube was sealed. The mixture was stirred at 98° C. with stirring for 20 h. The mixture was then concentrated and the residue was purified using reverse-phase HPLC (Gemini 5u C18(2) 100A, AXIA; 30×100 mm 5 micron; (30 mL/min, 7% ACN/H2O, 0.1% formic acid to 37% ACN/H2O, 0.1% formic acid) to give the title compound (65 mg, 54%) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.34 (m, 2H), 1.39 (d, J=6.57 Hz, 6H), 1.58-1.71 (m, 1H), 1.82 (d, J=11.87 Hz, 2H), 2.23-2.31 (m, 10H), 2.66 (td, J=11.94, 1.89 Hz, 2H), 3.57-3.71 (m, 2H), 4.70 (quin, J=6.63 Hz, 1H), 7.09 (d, J=2.02 Hz, 1H), 7.15 (dd, J=9.60, 1.52 Hz, 2H). MS: (M+H)+=358.2.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11](=[N:14][O:15][CH3:16])[O:12][CH3:13])=[C:9]([Cl:17])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([C:11](=[N:14][O:15][CH3:16])[O:12][CH3:13])=[C:9]([Cl:17])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: CON=C(OC)c1c(Cl)ccc(C(=O)O)c1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CON=C(OC)c1c(Cl)ccc(C(=O)Cl)c1Cl
Yield: 99.8 %

Procedure:
A solution of 2.10 g (0.0076 mol) of 2,4-dichloro-3-(1'-(methoxy)imino-1'-methoxymethyl)benzoic acid and 20.00 g of thionyl chloride in 50 ml of dry toluene was stirred for 2 hours at 80° C. After the solvent had been removed in vacuo, 2.25 g of 2,4-dichloro-3-(1'-methoxyimino-1'-(methoxy)methyl)benzoyl chloride were obtained.
Reaction SMILES: [Br:1][CH:2]([CH:14]([Br:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[CH2:13])[C:10]([OH:12])=[O:11].[CH3:24]O.B(F)(F)F>CO>[Br:1][CH:2]([CH:14]([Br:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[CH2:13])[C:10]([O:12][CH3:24])=[O:11]
Reactant: C=C(CCCCCCC(Br)C(Br)CCCCCCCC)C(=O)O
Reactant: CO
Agent: FB(F)F
Product: C=C(CCCCCCC(Br)C(Br)CCCCCCCC)C(=O)OC

Procedure:
The dibromo acid product obtained in Example V, 2-(7,8-dibromohexadecyl)-acrylic acid, is dissolved in 50 ml of methanol and 5 ml of boron trifluoride methanol solution is added. The solution is heated under reflux for 6 hrs. The solution is concentrated to 1/2 volume and the acid is neutralized with saturated NaHCO3 solution to about pH 7. The oily material is extracted with ether, washed with water and dried over Na2SO4. The ether solvent is removed under reduced pressure to give 4.80 g of crude oily product, methyl 2-(7,8-dibromohexadecyl)-acrylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.[N:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:24]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)([OH:26])[CH3:25])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cncs2)cc1
Reactant: CC(=O)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1ncc(-c2ccc(F)cc2)s1
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
To a solution of 5-(4-fluorophenyl)thiazole (0.1 g, 0.558 mmol) in dry THF (8 mL) at −78° C., was slowly added n-1.6 M BuLi in hexanes (0.7 mL, 1.117 mmol), the reaction mixture was stirred for 30 minutes and 1-(pyridin-4-yl)ethanone (0.13 mL, 1.117 mmol) in THF (8 mL) was added. The reaction mixture was stirred for 2 hours at −78° C., the reaction mixture quenched with saturated NH4Cl solution (50 mL), extracted with EtOAc (2×50 mL), the organic layer washed with water (50 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain crude product. The crude product was purified by preparative TLC (5% methanol in dichloromethane) to give 1-(5-(4-fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl)ethanol as off-white solid (35 mg, 22% yield) in 99.6% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (br s, 1H), 8.03 (s, 1H), 7.66-7.63 (m, 2H), 7.53 (br s, 2H), 7.24 (t, 2H), 6.99 (s, 1H), 1.89 (s, 3H); LC-MS m/z calculated for [M+H]+ 301.07. found 301.4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:21]3[CH:25]=[C:24]([CH3:26])[O:23][C:22]=3[CH3:27])/[CH:18]([CH3:20])[CH3:19])/[C:9]2=[O:28])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>ClCCl.C(N(CC)CC)C>[C:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:21]3[CH:25]=[C:24]([CH3:26])[O:23][C:22]=3[CH3:27])/[CH:18]([CH3:20])[CH3:19])/[C:9]2=[O:28])=[CH:4][CH:3]=1)(=[O:32])[CH:30]=[CH2:31]
Reactant: CC(C)=C1C(=O)N(c2ccc(O)cc2)C(=O)/C1=C(/c1cc(C)oc1C)C(C)C
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(N2C(=O)C(=C(C)C)/C(=C(\c3cc(C)oc3C)C(C)C)C2=O)cc1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution obtained by dissolving 1.13 g of n-(4-hydroxyphenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)isobutylidene]-3-isopropylidenesuccinimide obtained in Example 18 in 30 ml of dichloromethane, 0.62 ml of triethylamine, followed by dropwise addition of 0.36 ml of acryloyl chloride in 10 minutes. The reaction was carried out at room temperature for additional 30 minutes with stirring. After the reaction, the reaction solution was well washed with water, dried over anhydrous magnesium sulfate, and subjected to removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solvent of n-hexane and ethyl acetate) to give yellow crystals of N-(4-acryloyloxyphenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl) isobutylidene]-3-isopropylidenesuccinimide in yield of 60%.
Reaction SMILES: O.N[C:3]1[C:30](Cl)=[CH:29][C:6]([C:7]([NH:9][C@H]2CCN(CCCOC3C=CC(F)=CC=3)C[C@H]2OC)=[O:8])=[C:5]([O:32][CH3:33])[CH:4]=1>CO>[CH3:33][O:32][C:5]1[CH:4]=[CH:3][CH:30]=[CH:29][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC
Solvent: CO
Solvent: O
Product: COc1ccccc1C(N)=O

Procedure:
40 Parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate were boiled in 160 parts of methanol. The product was filtered off while hot and crystallized twice from a mixture of 600 parts of tetrachloromethane and 400 parts of trichloromethane. The product was filtered off, dried and recrystallized from 4-methyl-2-pentanone. The product was filtered off and dried (water-separator) yielding 18.5 parts of cis-4-amino-5-chloro-N-[2-chloro-4-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]aminocarbonyl]-5-methoxyphenyl]-2--methoxybenzamide; mp. 181.5° C. (compound 239).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cc1ccc(N)cc1F
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)OCC)c(F)c1

Procedure:
A solution of 8.2 g. of 2-fluoro-4-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hours. The solution is concentrated by distillation and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate dried and evaporated to yield ethyl 2-fluoro-4-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.4 g. of 1-bromohexadecane, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated at 80° C. for 7 hours. The mixture is then cooled, diluted with water, and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from a mixture of chloroform and hexane, yielding ethyl 2-fluoro-4-(hexadecylamino)phenylacetate.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][N:20]=[N+:21]=[N-:22])[O:7][C@@H:6]1Br)(=O)C.C1C([N+]([O-])=[O:31])=CC=C(O)C=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[C:49]([O:52]CC)(=[O:51])[CH3:50]>C(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[C:49]([O:52][C@H:6]1[O:7][C@H:8]([CH2:19][N:20]=[N+:21]=[N-:22])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C:5]1([OH:4])[OH:31])(=[O:51])[CH3:50]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)O[C@H](CN=[N+]=[N-])[C@@H]1OC(C)=O
Agent: [Ag+]
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@@H](CN=[N+]=[N-])O[C@H](OC(C)=O)C(O)(O)[C@H]1OC(C)=O
Reaction time: 1 h
Yield: 65 %

Procedure:
2,3,4-tri-O-acetyl-6-azido-6-deoxy-α-D-galactopyranosylbromide 37 (100 mg, 0.25 mmol) and p-nitrophenol (37 mg, 0.27 mmol) were dissolved in DCM. This solution was added to a stirred suspension of 2,6-di-tert-butyl-4-methyl-pyridine (37 mg, 0.18 mmol), silver triflate (87 mg, 0.30 mmol) and molecular sieves (3 Å) in DCM (7 ml). The reaction mixture was stirred under argon. After 1 h, t.1.c. (petrol:ethyl acetate, 2:1) indicated complete consumption of starting material (Rf 0.4). The reaction mixture was filtered through celite, concentrated in vacuo and co-evaporated with water. The residue was purified by flash column chromatography (DCM:ether, 30:1) to afford 1,3,4-tri-O-acetyl-6-azido-6-deoxy-2-hydroxy-α-b-galactopyranose 39 (55 mg, 65%) as a colourless oil (Rf 0.5); partial data [α]D25 +68.7 (c, 0.2 in CHCl3); νmax (thin film) 3432 (br, OH), 2101 (sh, N3) 1644 (st, C═O)cm−1; δH (400 MHz, CDCl3) 2.02, 2.03, 2.17, 2.18 (12H, 4 x s, 4 x CH3), 3.28 (11H, dd, J5,6 7.8 Hz, J6,6′ 10.3Hz, H-6), 3.35 (1H, dd, J5,6′ 6.2 Hz, H-6′), 4.31 (1H, m, H-5), 5.32 (1H, dd, J2,3 3.2 Hz, J2,3 11.0 Hz, H-2), 5.37 (1H, dd, J3,4 3.1 Hz, H-3), 5.69-5.70 (1H, m, H-4), 6.37 (1H, d, H-1); δC (100.6 MHz, CDCl3) 20.5, 20.6, 20.9 (3 x q, 3 x CH3), 27.4 (t, C-6), 66.2 (d, C-2), 67.5 (d, C-3), 67.7 (d, C-4), 71.2 (d, C-5), 89.6 (d, C-1), 168.9, 169.9, 170.1 (3 x s, 3 x C═O).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].O.[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:15]=1[C:16](Cl)=[O:17]>ClCCl>[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:15]=1[C:16]([NH:5][CH2:4][CH2:3][Cl:2])=[O:17]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: NCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(NCCCl)c1c(Cl)cccc1Cl
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a stirred (vigourously) mixture of 17.4 parts of 2-chloroethanamine hydrochloride, 20.7 parts of potassium carbonate and 225 parts of water was added dropwise a mixture of 31.3 parts of 2,6-dichlorobenzoyl chloride and 120 parts of dichloromethane at room temperature: slightly exothermic reaction. Upon completion, stirring at room temperature was continued for one hour. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated. The residue was crystallized from methylbenzene. The product was filtered off and dried, yielding 25.8 parts (68.8%) of 2,6-dichloro-N-(2-chloroethyl)benzamide; mp. 113.8° C. (intermediate 30).
Reaction SMILES: Cl[C:2]1[C:11](/[CH:12]=[CH:13]/[CH2:14][OH:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][O-:17].[Na+]>CO.C(OCC)(=O)C>[CH3:16][O:17][C:2]1[C:11](/[CH:12]=[CH:13]/[CH2:14][OH:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: OC/C=C/c1cc2ccccc2nc1Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1nc2ccccc2cc1/C=C/CO
Yield: 80 %

Procedure:
A mixture of (E)-3-(2-chloro-3-quinolinyl)-2-propen-1-ol (5.74 g) and sodium methoxide (28% in methanol; 10 ml) in MeOH (30 ml) was refluxed for 2 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The residue was washed with cyclohexane-i-Pr2O to give the titled compound (4.50 g; 80%) as a colorless solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[N:6]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9](=[O:16])[NH:8][C:7]1=[O:17].[F:18]F.[C:20]([OH:23])(=[O:22])[CH3:21]>>[C:20]([O:23][CH:11]1[N:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[C:7](=[O:17])[NH:8][C:9](=[O:16])[C:10]1([F:18])[C:12]([O:14][CH3:15])=[O:13])(=[O:22])[CH3:21]
Reactant: FF
Reactant: CC(=O)O
Reactant: COC(=O)c1cn(C2CCCO2)c(=O)[nH]c1=O
Product: COC(=O)C1(F)C(=O)NC(=O)N(C2CCCO2)C1OC(C)=O

Procedure:
In 200 ml. of glacial acetic acid is dissolved 1.38 g. of methyl 1-(2-tetrahydrofuryl)-1,2,3,4-tetrahydro-2,4-dioxopyrimidine-5-carboxylate and the fluorination is carried out at 18° C. to 24° C. using a gaseous mixture of fluorine (15 V/V %) and nitrogen. When the mixed gas equivalent to 2.2 moles of fluorine has been introduced, the absence of any residual starting material is confirmed by ultraviolet absorption spectrum. The solvent is then distilled off under reduced pressure to give a colorless syrup of methyl 6-acetoxy-5-fluoro-1-(2-tetrahydrofuryl)-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[CH2:10]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]#N)[CH2:16][CH2:15]1)[CH2:11][CH2:12][CH3:13].C(Cl)Cl.C[OH:29]>CCOCC.C(Cl)Cl>[CH2:10]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=2[CH3:9])=[O:29])[CH2:16][CH2:15]1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC1CCN(CCCC#N)CC1
Reactant: CO
Reactant: Cc1cccc(I)c1C
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC1CCN(CCCC(=O)c2cccc(C)c2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
In a 10 mL oven-dried flask was added Mg turnings (94 mg, 3.8 mmol) which was activated under vacuum by the use of a heat-gun. Under inert atmosphere was added a suspension of 1-iodo-2,3-dimethylbenzene (0.69 g, 3.0 mmol) in Et2O (5 mL) under spontaneously reflux, and the reaction mixture was allowed to reflux for 4 hours. A suspension of compound 4 (0.41 g, 2.0 mmol) in CH2Cl2 (2 mL) was added to the reaction mixture and left at rt overnight. The reaction mixture was quenched by addition of H2SO4 (7 mL, 2 M) and stirred at rt for 3 hours, followed by addition of NaOH (20 mL, 2 M) until basic conditions. The reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), and the organic phases were dried (MgSO4) and evaporated to dryness to produce 0.69 g of crude 19. The crude product was subjected to CC [eluent: CH2Cl2: MeOH (99:1)] to give pure 19 (0.40 g, 64%); LC-MS [M+H]+ 315 (cald. 315.5).
Reaction SMILES: [C:1]([O:5][C:6]1[C:13]([F:14])=[CH:12][C:9]([C:10]#[N:11])=[C:8](F)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Na].[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O1CCOCC1>CCOCC>[CH3:17][O:18][C:19](=[O:28])[CH:20]([C:8]1[C:9]([C:10]#[N:11])=[CH:12][C:13]([F:14])=[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:7]=1)[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: CC(C)(C)Oc1nc(F)c(C#N)cc1F
Reactant: COC(=O)CC(=O)OC(C)(C)C
Agent: [Na]
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)C(C(=O)OC(C)(C)C)c1nc(OC(C)(C)C)c(F)cc1C#N
Temperature: 95 °C
Reaction time: 14 h

Procedure:
A thick mixture of 6-tert-butoxy-2,5-difluoro-nicotinonitrile (18.22 g, 85.9 mmol), as prepared in Example 1b, malonic acid tert-butyl ester methyl ester sodium salt (34.49 g, 176 mmol), as prepared in the previous step, and dioxane (110 mL) was stirred under argon at 95° C. (oil bath) for 14 h. The resulting homogeneous dark amber solution was allowed to cool to rt, diluted with ether (150 mL), and washed with a solution of 1.0 M NaH2PO4 (200 mL) containing 2.0 M citric acid (40 mL). The aqueous layer was back-extracted with ether (1×100 mL), the organic layers were combined, washed with 4 M NaCl (1×100 mL), dried (Na2SO4), and concentrated under reduced pressure. Malonic acid tert-butyl ester methyl ester was largely removed from the residue by high vacuum at 95° C. for 1 h to afford the title compound as a clear, dark brown viscous oil (32.37 g, approx. 100% crude yield). 1H-NMR (300 MHz, CDCl3) δ 7.48 (d, 1H), 5.06 (s, 1H), 3.80 (s, 3H), 1.62 (s, 9H), 1.47 (s, 9H).