Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13][CH2:14][CH2:15][C:16]2[CH:31]=[CH:30][C:19]([O:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=3)=[CH:18][CH:17]=2)[CH2:8]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:6][C@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13][CH2:14][CH2:15][C:16]2[CH:31]=[CH:30][C:19]([O:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=3)=[CH:18][CH:17]=2)[CH2:8]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@H](NCCc2ccc(Oc3ccc(C(N)=O)cn3)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Oc2ccc(CCN[C@H]3CCC[C@H](O)C3)cc2)nc1
Reaction time: 4 h
Yield: 91.1 %

Procedure:
Treat (±)-(trans)-6-(4-{2-[3-(tert-butyldimethyl-silyloxy)cyclohexylamino]ethyl}phenoxy)nicotinamide (Example 451, Part C, 63.3 mg, 0.13 mmol) in THF (1.0 mL) with 1:0 M tetrabutylammonium fluoride (TBAF) in THF (0.5 eq) for 1 hour. Add another 0.5 eq of 1.0 M TBAF and stir for 4 hours. Add 1.0 eq of 1.0 M TBAF and stir for 9 days. Add another 1.0 eq of 1.0 M TBAF and stir for 4 days. Concentrate, dissolve the mixture in CH2Cl2 (20 mL), and wash with H2O (2×20 mL), saturated aqueous NaHCO3 and brine (20 mL each). Back-extract the aqueous layers with CH2Cl2 (20 mL). Concentrate the two H2O washings and purify by flash chromatography, eluting with 15% (2.0 M NH3 in MeOH) in CH2Cl2 to afford the title compound (42.1 mg, 88%): MS ES+ 356.4 (M+H)+, HRMS calcd for C21H28N3O2 356.1974 (M+H)+, found 356.1979, time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-99% over 19 min], tR=7.11 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1>>[NH2:26][CH2:25][C:3]1[C:2]([NH:1][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)=[N:15][C:6]2[N:7]([CH3:14])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: COc1ccc(F)cc1-c1c(C#N)c(N)nc2c1c(=O)n(C)c(=O)n2C
Reactant: COc1cccc(CBr)c1
Product: COc1cccc(CNc2nc3c(c(-c4cc(F)ccc4OC)c2CN)c(=O)n(C)c(=O)n3C)c1

Procedure:
The synthesis of title compounds started from Compound 70a and 1-(bromomethyl)-3-methoxybenzene, according to procedures described in the synthesis of Compound 56. MS [m+H] calc'd C25H27FN5O4 480; found 480.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15]C)=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2O)cc1
Reaction time: 1.5 h
Yield: 112.6 %

Procedure:
A suspension of 2-(3-chlorophenyl)-4-(methoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (6.26 g, 16 mmol) in 5% NaOH (54 mL) dioxane (39.4 mL) was heated at reflux and stirred for 1.5 hours. As the reaction proceeds, the solution becomes orange and homogeneous. The mixture was cooled and poured into 1N HCl, with constant stirring. The resulting white solid was filtered and rinsed with H2O and left to dry overnight. The mostly dry product was taken up in CH2Cl2 and azeotroped with toluene to remove any remaining H2O, to provide the desired product as a white solid (yield: 6.79 g, >100%). 1H NMR (300 MHz, DMSO d6) δ 2.27 (s, 3H), 7.51-7.62 (m, 2H), 7.68 (m, 1H), 7.79 (m, 1H), 8.03 (m, 4H), 8.24 (s, 1H). MS (DCI/NH3) m/z 377 (M+H)+, 396 (M+NH4)+.
Reaction SMILES: C(#N)C.[CH2:4]([O:6][C:7]([C:9]1[NH:13][N:12]=[C:11]([CH3:14])[CH:10]=1)=[O:8])[CH3:5].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH2:4]([O:6][C:7]([C:9]1[N:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[C:11]([CH3:14])[CH:10]=1)=[O:8])[CH3:5]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc(C)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
An acetonitrile (8.0 mL) mixture of ethyl-3-methyl-1H-pyrazole-5-carboxylate (15) (0.50 g. 3.2 mmol), benzyl bromide (0.48 mL, 4.0 mmol), and K2CO3 (0.90 g, 6.5 mmol) was stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After removal of solvent under reduced pressure, the residue was purified by flash column chromatography [silica gel, eluting with mixtures of ethyl acetate and hexanes (0% ramped to 15% EtOAc/hexanes)] to yield 0.30 g of ethyl-1-benzyl-3-methylpyrazole-5-carboxylate (16). 1H NMR (CDCl3): δ 7.30-7.22 (m, 5H), 6.65 (s, 1H), 5.71 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 2.32 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); LCMS: purity: 99%; MS (m/z): 345 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=[O:33])[NH:25][O:26]C3C=CC=CC=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=[O:33])[NH:25][OH:26])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(=O)C(Cc1ccc(-c2ccc(CCC(=O)NOc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)C(Cc1ccc(-c2ccc(CCC(=O)NO)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 97.3 %

Procedure:
Palladium on BaSO4 (5%, 1.0 g) was added to a degassed solution of the benzyl hydroxamate 47 (1.2 g) in MeOH (60 mL) and the suspension was treated with hydrogen at atmospheric pressure for 4 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 48 (1.0 g, 97%). 1H NMR (DMSO-d6): 10.42 (br, 1H), 7.55 (d, J=7.6 Hz, 4H), 7.32 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 1H), 4.57 (m, 1H), 2.94 (s, 3H), 2.73-2.91 (m, 7H), 2.29 (t, J=8.0 Hz, 2H), 1.31 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:16][C:17]1[S:18][C:19]([CH2:22]Br)=[CH:20][N:21]=1>>[Br:16][C:17]1[S:18][C:19]([CH2:22][N:10]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:20][N:21]=1
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Reactant: BrCc1cnc(Br)s1
Product: O=[N+]([O-])c1ccc(N(Cc2cnc(Br)s2)n2cnnc2)cc1

Procedure:
Starting Compounds: 4-(4-nitrophenyl)amino-4H-1,2,4-triazole and 2-bromo-5-(bromomethyl)thiazole
Reaction SMILES: C(OC1C(=O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N2CCN(C3CC3)C(=O)C=12)C1C=CC=CC=1.O[CH2:41][CH2:42][N:43]([CH:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1)[C:44]([C:46]1[C:51]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[C:50]([OH:60])[N:49]=[C:48]([CH2:61][C:62]2([C:67]3[C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[CH:70]=[CH:69][CH:68]=3)[CH2:66][CH2:65][CH2:64][CH2:63]2)[N:47]=1)=[O:45]>>[CH2:53]([O:52][C:51]1[C:50](=[O:60])[N:49]=[C:48]([CH2:61][C:62]2([C:67]3[C:76]4[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=4)[CH:70]=[CH:69][CH:68]=3)[CH2:66][CH2:65][CH2:64][CH2:63]2)[N:47]2[CH2:41][CH2:42][N:43]([CH:77]3[CH2:78][CH2:79][O:80][CH2:81][CH2:82]3)[C:44](=[O:45])[C:46]=12)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: O=C(c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CCOCC1
Agent: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1C1CC1
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1C1CCOCC1

Procedure:
This compound was prepared following the same method as described for pure 9-benzyloxy-2-cyclopropyl-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (356) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-(tetrahydro-pyran-4-yl)-amide (367) (110 mg, 0.2 mmol). Purification was done on silica gel (normal, 100-200 mesh) using 1% to 5% methanol in dichloromethane as gradient eluent. The yield was 96 mg, 90%, of a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][NH:7][C:8]([NH2:10])=[O:9].[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][NH:7][C:8](=[O:9])[NH:10][C:25]([NH:24][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[S:26]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC(=O)NCc1cccc(C(F)(F)F)c1
Solvent: CC(C)=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)NC(=S)NC(=O)c1ccccc1
Reaction time: 18 h

Procedure:
(3-Trifluoromethyl-benzyl)-urea (218 mg; 1.0 mmol) and 163 mg (1.0 mmol) benzoylisothiocyanate were dissolved in acetone and the mixture was heated to reflux. After 18 h of reflux HPLC-MS revealed almost complete conversion to expected product in a very clean reaction. The solvent was evaporated and the residue was dissolved in EtOAc (40 mL). Wash with 2M HCl (5 mL), water (2×5 mL) and brine (5 mL), and the organic phase was dried over MgSO4 and concentrated in vacuo to give 347 mg of a light yellow solid. HPLC-MS indicates a purity of approximately 90%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH3:10].C([O-])([O-])=O.[K+].[K+].[Br:17]N1C(=O)CCC1=O>C1COCC1.[Cl-].[Na+].O>[Br:17][C:9]1[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([CH3:10])=[N:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCn1ccnc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COCCn1c(Br)cnc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
To a solution of 1-(2-methoxyethyl)-2-methyl-1H-imidazole (Preparation 146, 604 mg, 4.31 mmol) in THF (8 mL), K2CO3 (119 mg, 0.86 mmol) was added and followed by N-Bromosuccinimide (652 mg, 3.66 mmol). The suspension was stirred at room temperature for 16 hours, diluted with brine and extracted with EtOAc. The organic layer was collected and concentrated in vacuo to afford the title compound as a yellow oil (219 mg, 26%) that was used directly in the next reaction.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2].S(=O)(=O)(O)O.[Br:17]N1C(=O)CCC1=O>>[Br:17][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([CH:1]=[O:2])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Br)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
Into a round bottom flask were combined 3-formylbenzoic acid (10.0 g, 66.6 mmol) and sulfuric acid (653 g, 6.66 mol). N-Bromosuccinimide (14.23 g, 79.9 mmol) was added portion wise over a 10 minute period and the reaction was stirred at room temperature for 3 h upon which the mixture was poured over ice. The white precipitate that formed was filtered, washed with cold water (5×100 mL), and recrystallized from water-ethanol to afford the title compound as a white solid (12.98 g, 76.6%). LC-MS: 227.0 [M−1]−; 1H NMR (400 MHz, DMSO-d6): 10.05 (s, 1H), 8.40 (t, 1H, J=1.5 Hz), 8.3 (d, 2H, J=1.5 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][N:20]([CH2:25][CH2:26][OH:27])[C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[OH:27][CH2:26][CH2:25][N:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][CH:16]=2)[C:21]1=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ccn(CCO)c(=O)c3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2cc(N3CCNCC3)ccc2ccn1CCO
Yield: 97.7 %

Procedure:
A solution of compound 7 (6 g, 16.1 mmol) in methylene chloride (20 mL) and trifluoroacetic acid (20 mL) was stirred at r.t for 1 h. Then the mixture was concentrated in vacuo to give the compound 8 (4.3 g, 98%)
Reaction SMILES: [Na].[CH3:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1>C(O)C>[CH3:2][C:3]([CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc2ccccc2c1)C(=O)OCC
Temperature: 0 °C

Procedure:
5.15 g (224 mmol) of sodium were dissolved in 150 ml of absolute ethanol, while heating, and 37.3 ml (217 mmol) of diethyl methylmalonate were added at room temperature. A solution of 50 g (217 mmol) of 2-bromomethylnaphthalene (96% pure) in 270 ml of ethanol was slowly added dropwise at 0° C., and the mixture was heated under reflux for a further 4 to 5 hours. It was poured onto ice-water and extracted with ethyl acetate. The combined organic phases were dried with sodium sulfate and evaporated. After drying under an oil pump vacuum, the oily residue was stirred with hexane at 0° C., whereupon 55 g (81%) of the compound 1 crystallized.
Reaction SMILES: [OH-].[Na+:2].[C:3]([OH:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[C:3]([O-:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na+:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
then adding a quantity of 2M aqueous sodium hydroxide (for quantity see table 5) at the same temperature as the stearic acid dispersion with stirring over a particular time (see table 5 for the time of addition) thereby producing a clear solution with a pH of about 9.2 substantially containing sodium stearate;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([F:28])[CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:40])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([F:28])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
70 mg (0.17 mmol) of the compound from Example 104 were introduced into 10 ml of dichloromethane at 0° C., 42 mg (0.17 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 76 mg (99% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH2:9].CCO[C:13]([S-])=[S:14].[K+]>C(O)C.O>[F:8][C:4]1[C:3]2[N:9]=[C:13]([SH:14])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(F)c1N
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Fc1cccc2[nH]c(S)nc12

Procedure:
1,2-diamino-3-fluorobenzene (1.6 g, 12.7 mmol) and potassium ethyl xanthogenate (2.64 g, 16.5 mmol) were dissolved in ethanol (25 ml) and water (6 ml). The mixture was refluxed for 14 hours and then concentrated on a rotavapor. Water (20 ml) was added and the solution was acidified with 2M hydrochloric acid. The precipitate was filtered off and dried. In this way the title compound was obtained (1.23 g, 58%). NMR is given below.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:20][O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Temperature: 0 °C
Yield: 14.4 %

Procedure:
Cytidine (100 g, 0.41 mol) was dissolved in warm dimethylformamide (65° C., 1125 mL). The solution was cooled with stirring to 0° C. A slow, steady stream of nitrogen gas was delivered throughout the reaction. Sodium hydride (60% in oil, washed thrice with hexanes, 18 g, 0.45 mol) was added and the mixture was stirred at 0° C. for 45 min. A solution of methyl iodide (92.25 g, 40.5 mL, 0.65 mol) in dimethylformamide (400 mL) was added in portions over 4 h at 0° C. The mixture was stirred for 7 h at 25° C. and then filtered. The filtrate was concentrated to dryness under reduced pressure followed by coevaporation with methanol (2×200 mL). The residue was dissolved in methanol (350 mL). The solution was adsorbed on silica gel (175 g) and evaporated to dryness. The mixture was slurried in dichloromethane (500 mL) and applied on top of a silica gel column (1 kg). The column was eluted with a gradient of dichloromethane-methanol (10:1®2:1). The less polar 2′,3′-dimethyl side product was removed and the coeluting 2′ and 3′-O-methyl product containing fractions were combined and evaporated under reduced pressure to a syrup. The syrup was dissolved in a minimum of hot ethanol (ca. 150 mL) and allowed to cool to 25° C. The resulting precipitate (2′ less soluble) was collected, washed with ethanol (2×25 ml) and dried to give 15.2 g of pure 2′-O-methylcytidine; mp 252–254° C. (lit. mp 252–254° C.); TLC homogenous (Rf 0.50, dichloromethane-methanol 3:1, (Rf of 3′ isomer is 0.50 and the dimethyl product is 0.80). The filtrate was evaporated to give 18 g of a mixture of isomers and sodium iodide.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([OH:20])[C:10]([CH:21]([CH3:23])[CH3:22])=[N:9]1.OC1C(C(C)C)=NNC(=O)[C:32]=1[C:41]([O:43]CC)=[O:42].[H-].[Na+].C1(C2C=CC=CC=2CBr)C=CC=CC=1.C[N:63](C)C=O>>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:13](=[O:14])[C:12]([C:15]([NH:63][CH2:32][C:41]([OH:43])=[O:42])=[O:16])=[C:11]([OH:20])[C:10]([CH:21]([CH3:23])[CH3:22])=[N:9]1.[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([OH:20])[C:10]([CH:21]([CH3:22])[CH3:23])=[N:9]1
Reactant: CCOC(=O)c1c(O)c(C(C)C)n[nH]c1=O
Reactant: CN(C)C=O
Agent: BrCc1ccccc1-c1ccccc1
Agent: CCOC(=O)c1c(O)c(C(C)C)nn(Cc2ccccc2-c2ccccc2)c1=O
Agent: [H-]
Product: CC(C)c1nn(Cc2ccccc2-c2ccccc2)c(=O)c(C(=O)NCC(=O)O)c1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethyl 2-(2-biphenylylmethyl)-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate. To a solution of ethyl 5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (example 46(a), 125 mg, 0.55 mmol) in N,N-Dimethylformamide (DMF) (5 ml) at 0° C. was added sodium hydride (55 mg, 0.138 mmol) in portions. The reaction mixture was stirred at room temperature for 45 minutes and then cooled back to 0° C. and 2-phenylbenzyl bromide (101 μl, 0.55 mmol) was added. The mixture was stirred at ambient temperature for 3 hours then quenched with 1N HCl (3 ml) extracted with ethyl acetate (2×20 ml). The organic layers were combined, dried over Magnesium sulfate, filtered and solvents removed with rotary evaporation. The crude oil was purified by flash column chromatography (10-100% ethyl acetate in hexanes) to provide the title compound ethyl 2-(2-biphenylylmethyl)-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (126 mg, 0.32 mmol, 58% yield) as a pale yellow oil that was used immediately in the next step. MS (ES+) m/e 393 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:18]O>>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:18])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1c(Br)ccc(F)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(Br)ccc(F)c1F
Temperature: 25 °C

Procedure:
A stirred solution of 6-bromo-2,3-difluorobenzoic acid and conc. H2SO4 in MeOH was heated at reflux for 18 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the residue was carefully added a satd. aq. NaHCO3 solution. The resulting mixture was extracted with CH2Cl2. The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was dried under high vacuum to afford the title compound. ESI MS (M+H) 251.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])[S:8][C:7]=2[CH:21]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:19][C:18](=[O:20])/[CH:17]=[CH:16]/[C:9]2[S:8][C:7]3[CH:21]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[C:10]=2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCc1c(/C=C/C(=O)O)sc2cc(OC)ccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)sc2cc(OC)ccc12
Yield: 82.8 %

Procedure:
As in Example 113, (E)-3-(6-methoxy-3-pentylbenzo[b]thien-2-yl)-2-propenoic acid (7 g) was reacted with 4-nitrophenol (3.6 g) in dichloromethane (70 mL) in the presence of 1,3-dicyclohexylcarbodiimide (4.8 g). The crude reaction product was crystallized from dichloromethane-2-propanol to give 8.1 g of (E)-3-(6-methoxy-3-pentylbenzo[b]thien-2-yl)-2-propenoic acid 4-nitrophenyl ester, mp 111°-113° C. Anal. Calcd for C23H23NO5S: C, 64.92; H, 5.45; N, 3.29; S, 7.54 Found: C, 64.64; H, 5.35; N, 3.27; S, 7.67
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[CH3:15][N:16](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:11]([F:14])([F:13])[CH2:10][O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)COCc1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(COCC(F)(F)F)cn1
Reaction time: 0.17 h
Yield: 50 %

Procedure:
2-Chloro-5-[(2,2,2-trifluoroethoxy)methyl]pyridine (Intermediate 227, 0.537 g, 2.38 mmol) was dissolved in DMF (6 mL) and zinc cyanide (0.279 g, 2.38 mmol) was added. The mixture was degassed by stirring under a flow of nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.275 g, 0.24 mmol) and further DMF (2 mL) were added and the mixture heated to 100 C in a sealed tube for 6 h. The mixture was partitioned between EtOAc (50 mL) and water (50 mL) and the organic layer washed with further water (2×50 mL). The organic layer was dried over sodium sulfate and concentrated to yield an orange oil. This was purified by FCC, eluting with a gradient of 0-30% EtOAc in heptane to afford the title compound as a colourless oil (0.255 g, 50%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.62 (1H, d), 7.79 (1H, dd), 7.66 (1H, d), 4.72 (2H, s) and 3.89 (2H, q).