Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([O:19][CH3:20])=[C:7]2[C:3]=1[C:4]1[CH:31]=[C:30]([CH3:32])[CH:29]=[N:28][C:5]=1[N:6]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[H-].[Na+].[CH3:35]I>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH3:35])[C:8]([O:19][CH3:20])=[C:7]2[C:3]=1[C:4]1[CH:31]=[C:30]([CH3:32])[CH:29]=[N:28][C:5]=1[N:6]2[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22]
Reactant: COc1c(NC(=O)OC(C)(C)C)cc(Br)c2c3cc(C)cnc3n(C(=O)OC(C)(C)C)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(N(C)C(=O)OC(C)(C)C)cc(Br)c2c3cc(C)cnc3n(C(=O)OC(C)(C)C)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
To a solution of Compound 249 (610 mg, 1.2 mmol) in dry DMF (3 mL) was added NaH (60 mg, 1.51 mmol) at 0° C. and the mixture was stirred for 20 min. To this ice cold reaction mixture was added MeI (0.72 ml, 1.44 mmol, 2 M solution) and stirred for another 30 min. at 0° C. Slowly the temperature was raised to room temperature and stirred for an additional hour. Reaction was quenched with water and extracted with ether, washed with brine, dried over Na2SO4 and finally purified flash chromatography to furnish Compound 250 (468 mg, 75%).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH:10]([CH:11]([O:22][C:23](=[O:25])[CH3:24])[CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:9][C:8]([C:26]([O:28][CH3:29])=[O:27])=[CH:7][CH:6]1[NH2:30])(=[O:3])[CH3:2].[N:31]#[C:32]F.N#CCl.N#CBr.N#CI>>[C:1]([NH:4][CH:5]1[CH:10]([CH:11]([O:22][C:23](=[O:25])[CH3:24])[CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:9][C:8]([C:26]([O:28][CH3:29])=[O:27])=[CH:7][CH:6]1[NH:30][C:32]#[N:31])(=[O:3])[CH3:2]
Reactant: COC(=O)C1=CC(N)C(NC(C)=O)C(C(OC(C)=O)C(COC(C)=O)OC(C)=O)O1
Reactant: N#CF
Agent: N#CBr
Agent: N#CCl
Agent: N#CI
Product: COC(=O)C1=CC(NC#N)C(NC(C)=O)C(C(OC(C)=O)C(COC(C)=O)OC(C)=O)O1

Procedure:
A] treating a compound of formula (V) with a cyanogen halide which may be selected from cyanogen fluoride, cyanogen chloride, cyanogen bromide or cyanogen iodide to obtain methyl 5-acetamido-4-cyanamido-6-(1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate (VIII); B] deacetylating the intermediate (VIII) to obtain methyl 5-acetamido-4-cyanamido-6-(1,2,3-trihydroxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate (IX). The reaction may be carried out in the presence of a deacetylating agent which may be selected from the group consisting of methanol/iodine, methanol/water, sodium t-butoxide, potassium carbonate, sodium hydroxide, or sodium methoxide; C] hydrolyzing the compound (IX) in a basic medium to obtain 5-acetamido-4-cyanamido-6-(1,2,3-trihydroxypropyl)-5,6-dihydro-4H-pyran-2-carboxylic acid of formula (VII). The base used in the reaction may be organic or inorganic. The organic base may be selected from the group consisting of pyridine, dimethylamine, trimethylamine and sodium ethoxide. The inorganic base may be selected from the group consisting of sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate; and D] reacting the compound (VII) with ammonium formate in the presence of ammonia which may be in the form of gaseous ammonia, liquid ammonia or aqueous ammonia and at a high temperature, for example ranging from 80° C. to 100° C., to obtain zanamivir (I).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1.Br[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>C(O)C>[OH:13][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9][CH:10]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(=O)COc1ccc(CO)cc1
Yield: 48.6 %

Procedure:
Mix potassium carbonate (2.764 g, 20 mmol), 4-hydroxy-benzyl alcohol (1.49 g, 12 mmol) in absolute ethanol (100 mL), add 1-bromopinacolone (1.791 g, 10 mmol) dropwise. Heat the mixture under reflux for 12 h. Add water to dissolve the solid, and remove most of the ethanol in vacuo. Extract the mixture with EtOAc three times. Combine the organic layers, wash with brine, dry over Na2SO4, filter and concentrate. Purify the residue by chromatography on silica gel eluting with EtOAc:hexane (1:2) to provide the desired intermediate as a colorless oil (1.08 g, 48%). MS (ES+) m/z: 205 M+H−H2O)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Cl[C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 96.1 %

Procedure:
To a solution of 91.3 grams (g) (0.56 moles) of 3,4-dichlorophenol dissolved in 500 milliliters (ml) of dimethyl sulfoxide (DMSO) was added 22.4 g (0.56 moles) of sodium hydroxide (NaOH). The slurry was heated at 60° C. for 15 minutes and 100 g (0.55 moles) of 2-chloro-5-nitrobenzonitrile was added. The mixture was heated at 75° C. for 3 hours (hrs). The reaction mixture was cooled and poured into a slurry of 200 ml of 2 normal (2 N) NaOH and 1800 ml of ice and water with the product precipitating. The product was collected by filtration, washed well with water and dried, to obtain 163.3 g of product (96.4% yield), mp 154°-155° C. Recrystallization from 3-methoxy-2-propanol (Dowanol® PM The Dow Chemical Company, Midland, Michigan) afforded purified 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile, melting at a melting point (mp) of 155°-156° C. The prominent infrared bands for 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile were as follows: IR (Nujol) 2250, 1620, 1580, 1520, 1465, 1360, 1270, 1130, 1040 and 895 cm-1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CC1C=CC(S(O[CH2:18][C@@H:19]([C@@H:33]2[C@:50]3([CH3:51])[C@H:36]([C@H:37]4[C@H:47]([CH2:48][CH2:49]3)[C@:45]3([CH3:46])[C:40]([CH2:41][C@@H:42]([O:59][CH:60]5[CH2:65][CH2:64][CH2:63][CH2:62][O:61]5)[CH2:43][C@@H:44]3[O:52][CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][O:54]3)=[CH:39][CH2:38]4)[CH2:35][CH2:34]2)[CH2:20][CH2:21][C@@H:22]([F:32])[C:23]([O:26][CH:27]([O:29][CH2:30][CH3:31])[CH3:28])([CH3:25])[CH3:24])(=O)=O)=CC=1>O1CCCC1>[O:54]1[CH2:55][CH2:56][CH2:57][CH2:58][CH:53]1[O:52][C@@H:44]1[C@@:45]2([CH3:46])[C:40](=[CH:39][CH2:38][C@@H:37]3[C@@H:47]2[CH2:48][CH2:49][C@@:50]2([CH3:51])[C@H:36]3[CH2:35][CH2:34][C@@H:33]2[C@H:19]([CH3:18])[CH2:20][CH2:21][C@@H:22]([F:32])[C:23]([O:26][CH:27]([O:29][CH2:30][CH3:31])[CH3:28])([CH3:25])[CH3:24])[CH2:41][C@@H:42]([O:59][CH:60]2[CH2:65][CH2:64][CH2:63][CH2:62][O:61]2)[CH2:43]1
Reactant: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 0.710 g. (0.0187 mole) of lithium aluminum hydride, 80 ml. of tetrahydrofuran and 4.85 g. (0.0057 mole) of [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate) was heated at reflux (60° C.) for 1 hr and cooled to 0° C. The mixture was diluted with 200 ml. of ether and quenched with the dropwise addition of 1.4 ml. of water and 1.1 ml. of 10% aqueous sodium hydroxide solution. The mixture was then stirred for 1 hr and filtered. The solids were triturated with ether and filtered. The combined filtrates were evaporated to dryness and chromatographed on 0.06-0.20 mm silica gel to yield [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-ene, [α]D20 +7° (c 1, CHCl3 ).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.[CH3:20][N:21]([CH3:30])[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>>[CH3:20][N:21]([CH3:30])[C:22]([N:24]1[CH2:25][CH2:26][N:27]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[C:8]=2[CH3:13])[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CN(C)C(=O)N1CCNCC1
Product: Cc1c(CN2CCN(C(=O)N(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
Reaction between 2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and piperazine-1-carboxylic acid dimethylamide (Example 26) using General Procedure B-3 yielded 4-(2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid dimethylamide.
Reaction SMILES: CC(C)C(N)=O.[OH-].[Na+].CN1C2C(=CC=CC=2)C(C2C(=O)N(C)C(=O)C=2Cl)=C1.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38]2[C:43](=[O:44])[N:42]([CH3:45])[C:40](=[O:41])[C:39]=2[C:46]2C=C[CH:49]=[CH:48][CH:47]=2)=[CH:30]1.Cl.O>O>[CH3:49][CH2:48][CH2:47][CH2:46][C:39]1[C:40](=[O:41])[N:42]([CH3:45])[C:43](=[O:44])[C:38]=1[C:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]([CH3:28])[CH:30]=1
Reactant: CN1C(=O)C(c2ccccc2)=C(c2cn(C)c3ccccc23)C1=O
Agent: CC(C)C(N)=O
Agent: CN1C(=O)C(Cl)=C(c2cn(C)c3ccccc23)C1=O
Agent: Cl
Solvent: O
Product: CCCCC1=C(c2cn(C)c3ccccc23)C(=O)N(C)C1=O
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
Into dimethylacetoamide (30 ml) was dispersed sodium hydroxide (content: 60%, 0.88 g, 22 mmol). To this were added IM-3 obtained in Example 1-2 (1.77 g, 10 mmol)/dimethylacetoamide (5 ml). This mixture was stirred for 10 minutes, then, to this was added IM-5 (4.5 g, 11 mmol) obtained as described above, and this mixture was stirred for three hours. To this was added water (10 ml), and this mixture was acidified with 1N water hydrochloride, and the reaction solution was concentrated. The concentrated mixture was refined with silica gel column chromatography to obtain 2.8 g of IM-6.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]1([C:3]2[C:2]([N:33]3[CH2:32][CH2:31][N:30]([C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:36])([F:37])[F:22])=[CH:29][CH:28]=4)[CH2:35][CH2:34]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(C(F)(F)F)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in DMF (8 mL), 1-(4-(trifluoromethyl)phenyl)piperazine (202 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv) were placed in a 20-mL sealed tube and stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 4×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate followed by filtration to remove solids. The resulting mixture was concentrated under vacuum, resulting in 177.4 mg (78%) of methyl 2-phenyl-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[CH:11]([CH3:13])[CH3:12].C1COCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.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].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH2:16]([O:15][C:10](=[O:14])[C:11]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1)([CH3:13])[CH3:12])[CH3:17]
Reactant: CCOC(=O)C(C)C
Reactant: COc1cccc(Br)n1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)c1cccc(OC)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 64.4 %

Procedure:
2-Bromo-6-methoxypyridine (7.0 g), ethyl isobutyrate (4.75 g), tri t-butylphosphine (300 mg) and Pd2(dba)3 (680 mg) were dissolved in toluene (200 ml) under nitrogen atmosphere, added with THF solution of LiHMDS (1.6 M, 24 ml), and the mixture was stirred at 100° C. for 6 hrs. The reaction mixture was diluted with ethyl acetate (300 ml), and washed three times with 15% brine (200 ml). The organic layer was concentrated under reduced pressure and the resulting residues were purified by silica gel column (n-hexane/ethyl acetate=4/1) to obtain the title compound (5.353 g, yield 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].I[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]=1[O:12][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: IC1CCCC1
Reactant: COC(=O)c1cc(O)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OC2CCCC2)c(OC2CCCC2)c1
Temperature: 70 °C
Reaction time: 46 h
Yield: 85.1 %

Procedure:
A mixture of methyl 3-chloro-4,5-dihydroxybenzoate (3) (300 mg, 1.48 mmol), iodocyclopentane (558 μL, 4.44 mmol) and potassium carbonate (614 mg, 4.44 mmol) in DMF (10 mL) was stirred at 70° C. for 46 h. The reaction mixture was cooled to room temperature and then partitioned between 1M HCl (75 mL) and EtOAc (100 mL). The phases were separated and the organic phase was washed with brine (2×75 mL) then dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (40 g, 0-100% EtOAc in isohexane) to give methyl 3-chloro-4,5-bis(cyclopentyloxy)benzoate (4) (427 mg, 1.26 mmol, 85% yield): m/z 339 [M+H]+ (ES+); 1H NMR (400 MHz, CDCl3) δ: 7.66 (1H, d), 7.45 (1H, d), 5.05-4.98 (1H, m), 4.87-4.83 (1H, m), 3.89 (3H, s), 1.95-1.55 (16H, m).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:29][C:30]#[N:31]>C(C(CC)=O)C>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([O:17][CH2:29][C:30]#[N:31])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: N#CCBr
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: N#CCOc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl

Procedure:
4.52 g of 3-chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydroindazole in 10 ml of diethyl ketone were added dropwise at approximately 20° C. to a suspension of 2.07 g of potassium carbonate and 2.49 g of potassium iodide in 150 ml of diethyl ketone. The reaction mixture was subsequently treated with 1.86 g of bromoacetonitrile in 10 ml of diethyl ketone. After the mixture had been refluxed for 10 hours, it was cooled, and the solvent was then removed. The residue was taken up in water, whereupon the solids formed were removed, washed with water and finally dried under reduced pressure at approximately 20° C. Yield: 3.20 g
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([O:13][CH:14]([CH2:24][CH3:25])[C:15]([NH:17][C:18]([CH3:23])([CH3:22])[C:19]#[C:20][CH3:21])=[O:16])[CH:10]=[N:11][CH:12]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C.CCCCCC>ClCCl.O1CCCC1>[C:6]([C:7]1[CH:8]=[C:9]([O:13][CH:14]([CH2:24][CH3:25])[C:15]([NH:17][C:18]([CH3:23])([CH3:22])[C:19]#[C:20][CH3:21])=[O:16])[CH:10]=[N:11][CH:12]=1)#[CH:5]
Reactant: CC#CC(C)(C)NC(=O)C(CC)Oc1cncc(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: C#Cc1cncc(OC(CC)C(=O)NC(C)(C)C#CC)c1
Reaction time: 18 h

Procedure:
The product from Stage 1 (0.4 g) was dissolved in dichloromethane (10 ml) with stirring and a solution of tetra n-butylammonium fluoride in tetrahydrofuran (1.4 ml, 1M) was added. The mixture was stirred at ambient temperature for 2 hours then stored for 18 hours. Further dichloromethane was added and the organic phase was washed with water (twice), dried over magnesium sulphate and evaporated under reduced pressure to give a gum that was fractionated by chromatography (silica; diethyl ether/hexane, 2:1 by volume) to give the required product, 0.21 g, as a pale brown oil.
Reaction SMILES: C(O)(=O)C.NN.C([O:10][C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15])(=O)C>C1COCC1>[C:14]([O:13][C@@H:12]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:28][CH:11]1[OH:10])(=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: NN
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
Under nitrogen atmosphere, hydrazine acetate (197 mg, 2.19 mmol, 1.4 equiv) was added to a solution of β-D-galactopyranose pentaacetate (605 mg, 1.55 mmol) in anhydrous THF (10 mL) in presence of 4 Å molecular sieve. The reaction mixture was stirred at room temperature for 4 h 30, filtered, concentrated to dryness under reduced pressure and purified by chromatography on silica gel (25:1, dichloromethane/methanol) to afford 2,3,4,6-tetra-O-acetyl-D-galactopyranose (528 mg, 98%) as a yellow oil which was directly used in the next step. Under nitrogen atmosphere, trichloroacetonitrile (1.34 mL, 13.4 mmol, 8.8 equiv) and potassium carbonate (1.42 g, 10.3 mmol, 6.7 equiv) were added to a solution of 2,3,4,6-tetra-O-acetyl-D-galactopyranose (528 mg, 1.52 mmol) in anhydrous dichloromethane (20 mL) in presence of 4 Å molecular sieve. The reaction mixture was vigourously stirred at room temperature for 12 h, filtered and concentrated to dryness under reduced pressure to afford 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl trichloroacetamidate (707 mg, 95%) which was used without further purification.
Reaction SMILES: O[C@@H]1C(C)(C)OC2C=CC(C#N)=CC=2[C@H]1N1C=CC(CO[Si](C(C)(C)C)(C)C)=CC1=O.O[C@@H:33]1[C:38]([CH3:40])([CH3:39])[O:37][C:36]2[CH:41]=[CH:42][C:43]([C:45]([F:48])([F:47])[F:46])=[CH:44][C:35]=2[C@H:34]1[N:49]1[CH:54]=[CH:53][C:52]([CH2:55][O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])=[CH:51][C:50]1=[O:64]>>[F:48][C:45]([F:46])([F:47])[C:43]1[CH:42]=[CH:41][C:36]2[O:37][C:38]([CH3:39])([CH3:40])[CH:33]=[C:34]([N:49]3[CH:54]=[CH:53][C:52]([CH2:55][O:56][Si:57]([C:60]([CH3:62])([CH3:63])[CH3:61])([CH3:59])[CH3:58])=[CH:51][C:50]3=[O:64])[C:35]=2[CH:44]=1
Reactant: CC1(C)Oc2ccc(C(F)(F)F)cc2[C@@H](n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)[C@@H]1O
Agent: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)[C@@H]1O
Product: CC1(C)C=C(n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)c2cc(C(F)(F)F)ccc2O1

Procedure:
The reaction and after treatment of Example 8 are repeated, except that the trans-3-hydroxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran used in Example 8 is replaced with the trans-3-hydroxy-6-trifluoromethyl-3,4-dihydro-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 50. Thus, 6-trifluoromethyl-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran is obtained.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[S:12]1[C:16]2[CH:17]=[C:18]([N:21]3[CH2:25][CH2:24][N:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][C:31]=4[CH:32](OC)[O:33]C)[C:22]3=[O:37])[CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1.CO>CC(C)=O.O.C(Cl)(Cl)Cl>[S:12]1[C:16]2[CH:17]=[C:18]([N:21]3[CH2:25][CH2:24][N:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][C:31]=4[CH:32]=[O:33])[C:22]3=[O:37])[CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: COC(OC)c1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: O=Cc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.3 %

Procedure:
PTSA (2.2 g, 11.672 mmol) was added to a stirred solution of 1-benzothiazol-6-yl-3-(4-dimethoxymethyl-pyridin-3-yl)-imidazolidin-2-one (I-177a: 460 mg, 1.2418 mmol) in acetone (20 mL) and water (20 mL). The resulting reaction mass was stirred for 48 hours at room temperature. The reaction was monitored by TLC (5% methanol in chloroform). The reaction mixture was concentrated, the residue was diluted with ice-water, basified with saturated NaHCO3 solution and extracted using ethyl acetate. The aqueous layer was filtered and the solid collected was dried under reduced pressure. The solid was dissolved in methanol and chloroform, dried over Na2SO4 and concentrated under reduced pressure to afford 400 mg of the product (99.5% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:17]>C(O)(=O)C.C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:8]=2[NH:9][C:10](=[O:12])[CH3:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1ccccc1-c1ccccc1
Reactant: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1ccc(Br)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
2-Phenyl-N-acetylaniline (6.21 g, 29.40 mmol) was dissolved in acetic acid (70 mL). Thereto was dropwise added under ice bath a separately prepared solution of hydrogen bromide (6.14 g, 38.42 mmol) dissolved in carbon tetrachloride (19.21 mL) and the mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure, to the residue was added water (20 mL) and subsequently ethanol (30 mL), and the mixture was stirred under ice bath for 1 hour. The precipitate was collected by filtration, washed with ethanol/water (=1:1), dried under reduced pressure to obtain 2-phenyl-4-bromo-N-acetylaniline (7.79 g).
Reaction SMILES: NN.[C:3]([O:7][C:8]([NH:10][C:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[CH:14][N:13]([CH2:24][CH2:25][CH2:26][N:27]2C(=O)C3C=CC=CC=3C2=O)[CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CCO>[NH2:27][CH2:26][CH2:25][CH2:24][N:13]1[CH:14]=[C:15]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)[C:11]([NH:10][C:8]([O:7][C:3]([CH3:4])([CH3:6])[CH3:5])=[O:9])=[CH:12]1
Reactant: CCc1ccc(-c2cn(CCCN3C(=O)c4ccccc4C3=O)cc2NC(=O)OC(C)(C)C)cc1
Agent: NN
Solvent: CCO
Product: CCc1ccc(-c2cn(CCCN)cc2NC(=O)OC(C)(C)C)cc1

Procedure:
Hydrazine (5 eq) was added to a solution of (tert-butoxy)-N-{1-[3-(1,3-dioxobenzo[c]azolin-2-yl)propyl]-4-(4-ethylphenyl)pyrrol-3-yl}carboxamide (1 eq) in abs. EtOH at 50° C. for 2 hours. The reaction developed a white precipitate which was filtered off. The EtOH was concentrated under reduced pressure. The residue was taken up in CH2Cl2 and the precipitate was filtered again. The organic solution was evaporated to a yellow solid containing product and solvent. Assumed a quantitative yield.