Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:40])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[N:39]=[C:10]2[C:11]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)=[C:12]([CH3:28])[C:13]([C:15]3[N:19]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)[N:18]=[CH:17][CH:16]=3)=[CH:14][N:9]2[N:8]=1.[CH3:41][O:42][S:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:45])=[O:44]>CC(C)=O>[C:46]1([S:43]([O-:45])(=[O:44])=[O:42])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[C:24]([C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:15]([C:13]3[C:12]([CH3:28])=[C:11]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=4)[C:10]4[N:9]([N:8]=[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N+:2]([CH3:41])([CH3:1])[CH3:40])[N:39]=4)[CH:14]=3)=[CH:16][CH:17]=[N:18]2)=[CH:27][CH:26]=1)#[N:25]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: COS(=O)(=O)c1ccccc1
Solvent: CC(C)=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCC[N+](C)(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Product: O=S(=O)([O-])c1ccccc1
Temperature: 55 °C
Yield: 89.3 %

Procedure:
To a solution of 4-{5-[2-(3-dimethylamino-propylamino)-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 28, 55 mg, 0.10 mmol) in acetone (0.44 mL) was added methylbenzenesulfonate (15 μL, 0.11 mmol) at ambient temperature. The reaction mixture was heated 55° C. for 1.5 hrs. The cooled reaction mixture was concentrated in vacuo to give a clear colorless oil. The oil thus obtained was triturated in diethyl ether and the resultant solid taken up in minimal EtOAc and Et2O added until a white solid formed. The precipitate was collected by filtration, washed with Et2O and dried in vacuo to yield the title compound as a white solid (64 mg).
Reaction SMILES: [CH2:1]([C@:3]1([OH:41])[C:38]2[CH:37]=[C:36]3[N:9]([CH2:10][C:11]4[C:12]3=[N:13][C:14]3[CH:15]=[CH:16][C:17]([F:35])=[C:18]5[CH:23]([N:24]6C(=O)C7C(=CC=CC=7)C6=O)[CH2:22][CH2:21][C:20]=4[C:19]=35)[C:8](=[O:39])[C:7]=2[CH2:6][O:5][C:4]1=[O:40])[CH3:2].O.NN.C(Cl)(Cl)[Cl:46]>CO>[ClH:46].[NH2:24][CH:23]1[C:18]2[C:19]3[C:20](=[C:11]4[CH2:10][N:9]5[C:36](=[CH:37][C:38]6[C@:3]([CH2:1][CH3:2])([OH:41])[C:4](=[O:40])[O:5][CH2:6][C:7]=6[C:8]5=[O:39])[C:12]4=[N:13][C:14]=3[CH:15]=[CH:16][C:17]=2[F:35])[CH2:21][CH2:22]1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccc(F)c3c1c2CCC3N1C(=O)c2ccccc2C1=O
Reactant: ClC(Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccc(F)c3c1c2CCC3N
Product: Cl

Procedure:
120 mg of the compound prepared in (11) above was dissolved in a mixed solvent of 7 ml of chloroform and 5 ml of methanol. After the addition of 0.7 ml of hydrazine monohydrate, the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated to dryness and to the residue was added 7 ml of 4N hydrochloric acid, and the mixture was heated under reflux for 1 hour. After concentration to dryness, 10 ml of water to the residue to remove the insoluble substances by filtration. The filtrate was purified in the same manner as in Example 7 to obtain 32 mg of Isomer A and 20 mg of Isomer B of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:24])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1.C(OO)(=[O:27])C>>[O:27]1[C:19]([CH3:24])([CH2:20][CH:21]([CH3:22])[CH3:23])[CH:18]1[CH2:17][CH2:16][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1
Reactant: CC(=O)OO
Reactant: CC(=CCOc1ccc2c(c1)OCCC2)CCC=C(C)CC(C)C
Product: CC(=CCOc1ccc2c(c1)OCCC2)CCC1OC1(C)CC(C)C

Procedure:
Following the procedure of Example 17, 7-(3,7,9-trimethyl-2,6-decadienyloxy)-chromane and peracetic acid are reacted to form 7-(6,7-epoxy-3,7,9-trimethyl-2-decenyloxy)-chromane, nD20 = 1.5256.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].Cl>O>[CH2:13]([O:12][C:10]([NH:1][CH:2]([CH:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Product: CC(O)C(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 18 h
Yield: 102.8 %

Procedure:
To a solution of D-threonine (50.7 g, 0.426 mol) in water (800 ml) at about 0° C. was added benzyl chloroformate (66 ml, 0.462 mol) dropwise over about 15 minutes. The reaction was allowed to warm to about 23° C. and was stirred at that temperature for about 18 hours. The reaction was cooled with ice and acidified with concentrated hydrochloric acid, extracted with ether (3 times) and the organic layers were concentrated to give 110.9 g of 2-benzyloxycarbonylamino-3-hydroxy-butyric acid as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17](Cl)=[O:18])=[CH:11][CH:10]=1.Cl.[CH2:21]1[CH2:25]OC[CH2:22]1>CCOCC>[CH2:25]([CH:7]1[CH2:8][C:3](=[O:2])[CH:4]=[CH:5][N:6]1[C:17]([O:16][CH2:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)=[O:18])[CH:21]=[CH2:22]
Reactant: COc1ccncc1
Reactant: C1CCOC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: C=CCC1CC(=O)C=CN1C(=O)OCc1ccccc1
Temperature: -23 °C
Reaction time: 0.5 h

Procedure:
At −23° C., to a solution of 4-methoxypyridine (5.45 g, 50 mmol) in THF (50 mL), 1.0 N Allyl-MgBr (50 mL, 50 mmol) in ether was added to form a yellow suspension. 95% Cbz-Cl (7.4 mL, 50 mmol) was then added dropwise. The yellow mixture was stirred at −23° C. for 30 mins and then poured into 10% HCl (100 mL). The reaction mixture was extracted with ethyl acetate. After removal of solvent, the crude product was purified by silica gel chromatography (gradient, 10% to 25% EtOAc/hexanes) to give benzyl 2-allyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate 129. LC/MS RT (2.25 min method)=1.090 min. Mass observed: 272.1 (M+H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:20](Cl)=[O:21].C(N(C(C)C)CC)(C)C>ClCCl>[N+:26]([C:25]1[CH:24]=[CH:23][C:19]([C:20]([N:6]2[CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:21])=[CH:18][C:17]=1[CH3:16])([O-:28])=[O:27]
Reactant: Cc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
A mixture of 1.17 g of 6,11-dihydro-5H-di-benz[b,e]azepine, 1.20 g of 3-methyl-4-nitrobenzoyl chloride, 0.80 ml of diisopropylethylamine in 25 ml of dichloromethane is stirred 18 hours at room temperature. The mixture is washed with water and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and diluted while hot with hexane to give 1.40 g of crystals. Recrystallization from dichloromethane-hexane gives 1.26 g of crystals, m.p. 179°-180° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:18])[CH:4]=[CH2:5].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].O>CN(C)C=O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][C:6]1([CH2:3][CH:4]=[CH2:5])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:18])[CH3:25]
Reactant: C=CCC1C(=O)CCc2ccc(OC)cc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC1(CC(=O)OCC)C(=O)CCc2ccc(OC)cc21
Reaction time: 1 h

Procedure:
Into a flame-dry 500 ml 3-neck flask provided with mechanical stirrer, dropping funnel and a nitrogen inlet tube was placed 4.21 g sodium hydride (55% dispersion in oil, 100 mmol) with the apparatus placed under nitrogen. The oil was washed out with benzene (3×30 ml), 40 ml dry dimethylformamide was added and the suspension was stirred and cooled in an ice-bath. A solution of 21.6 g (100 mmol) 1-allyl-3,4-dihydro-7-methoxy-2(1H)naphthalenone (VIIIa) in 10 ml dimethylformamide was added dropwise (10 min), then the cooling bath was removed and stirring at room temperature continued until the evolution of gas ceased (2 hr). The brown-colored reaction mixture was cooled (ice-bath) and a solution of 16.7 g (100 mmol) ethyl bromoacetate in 40 ml dimethylformamide was added dropwise keeping the reaction temperature below 25° C. After the addition (15-20 min) stirring in cold was continued for 1 hr and then overnight at room temperature. Water (300 ml) was added and extracted with ether (3×100 ml). The combined ether extracts were washed with water (2×100 ml) dried (MgSO4), the solvent removed by evaporation and the residue was distilled to give 26.0 g (86%) IXa, b.p. 145°-150°/0.05-0.01 mm Hg; IR (neat) 1740, 1715 cm-1 ; NMR δ, 1.05 and 3.92 (triplet and quartet for OCH2CH3), 3.75 (s, 3, OCH3), 4.65-6.0 (m, 3, CH=CH2), 6.55-7.15 (m, 3, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[F:42][C:43]1[C:48](O)=[C:47]([F:50])[C:46]([F:51])=[C:45]([F:52])[C:44]=1[F:53]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH:10]=[C:11]([C:13]([O:15][C:48]2[C:47]([F:50])=[C:46]([F:51])[C:45]([F:52])=[C:44]([F:53])[C:43]=2[F:42])=[O:14])[N:12]=1
Reactant: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Step 1, 2-(2-Chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic acid (1.5 g, 4.5 mmol) was dissolved in dichloromethane (40 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 946 mg, 4.95 mmol) and triethylamine (500 mg, 4.95 mmol) were added followed by pentafluorophenol (815 mg, 4.37 mmol). The mixture was stirred at rt under argon for one hour before it was washed with 5% HCl, sodium bicarbonate solution, and then brine. The organic layer was dried (MgSO4), filtered, and concentrated to give the crude product (1.26 g) which was chromatographed over silica gel (20% EtOAc in hexanes) to afford pentafluorophenyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate (0.73 g, 32% yield): LC-MS m/z 499.0 (MH+), retention time 3.93 min (method 1).
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[OH-].[Li+].C(OCC)(=O)C.Cl>O1CCCC1.O>[CH2:18]([O:17][C:15]([NH:14][C@H:4]([CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9])[C:3]([OH:25])=[O:2])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To (R)-2-Benzyloxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-propionic acid methyl ester (1.450 g, 3.95 mmol) in tetrahydrofuran/water (2/1) is added lithium hydroxide (250 mg, 5.92 mmol). After stirred at rt during 16 h, the solution is treated with ethyl acetate and the pH is decrease to 2 with aqueous 1N HCl. The organic phase is dried and evaporated to yield the title compound.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:34])[C:11]2[O:17][C:16]3[C:18]([Cl:30])=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:21][C:15]=3[CH2:14][S:13](=[O:32])(=[O:31])[C:12]=2[CH:33]=1)=[O:7].FC(F)(F)C(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:34])[C:11]2[O:17][C:16]3[C:18]([Cl:30])=[CH:19][C:20]([N:22]([CH2:1][CH3:2])[CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:21][C:15]=3[CH2:14][S:13](=[O:31])(=[O:32])[C:12]=2[CH:33]=1)=[O:7]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCC3)cc(Cl)c1O2
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCN1CCCC1)c1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Distilled acetaldehyde (0.11 mL, 1.90 mmol) was added to a solution of Example 72k (0.180 g, 0.38 mmol) in dry methanol (15 mL), followed by the addition of trifluoroacetic acid (0.03 mL, 0.38 mmol). The reaction mixture was stirred at 0° C. for 2 h. Sodium cyanoborohydride was added and the reaction mixture was allowed to come to room temperature and then left stirring overnight. It was concentrated, treated with 10% aqueous sodium bicarbonate solution, water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.118 g (62%); 1H NMR (DMSO-d6): δ 1.20 (t, 3H, CH3), 1.90-2.00 (m, 4H, 2CH2), 2.60-2.69 (m, 4H, 2CH2), 2.70 (s, 3H, CH3), 3.45 (q, 2H, CH2), 3.55 (t, 2H, CH2), 3.90 (s, 3H, OCH3), 4.70 (s, 2H, CH2), 6.65 (s, 1H, Ar), 6.75 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.55 (s, 1H, Ar); MS: m/e (ES+) 493 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)=[C:17]([F:28])[CH:16]=2)=[N:4][CH:5]=[N:6][CH:7]=1.[OH2:29].CC#N.C(Cl)[Cl:34].[OH2:36]>>[ClH:34].[NH2:1][C:2]1[C:3]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][C:24]([NH2:27])=[N:23][CH:22]=3)=[C:17]([F:28])[CH:16]=2)(=[O:36])=[O:29])=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: ClCCl
Reactant: Nc1ncc(-c2ccc(-c3ccccc3Sc3ncncc3N)cc2F)cn1
Reactant: O
Solvent: CC#N
Product: Cl
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)c3ncncc3N)cc2F)cn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 5-{2′-[(5-aminopyrimidin-4-yl)sulfanyl]-3-fluorobiphenyl-4-yl}-pyrimidin-2-amine (200 mg, 0.51 mmol) in MeCN/DCM/H2O (5 mL/5 mL/5 mL) were added NaIO4 (326 mg, 1.50 mmol) and RuCl3 (16 mg, 0.075 mmol). The reaction mixture was stirred at rt for 10 hours then poured into water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic extracts were concentrated and purified by HPLC to give the title compound as a white solid. MS (ESI): mass calcd. for C20H15FN6O2S, 422.10; m/z found, 423.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 2H), 8.30-8.25 (m, 2H), 8.22 (s, 1H), 7.83 (m, 1H), 7.77 (m, 1H), 7.44-7.33 (m, 2H), 6.88 (d, J=9.5, 2H), 6.29 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:20])[NH:6]1.[H-].[Na+].[CH3:24]I>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:20])[N:6]1[CH3:24]
Reactant: COC(=O)CC1NC(=O)N(Cc2ccc(OC)cc2)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC1C(=O)N(Cc2ccc(OC)cc2)C(=O)N1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.3 %

Procedure:
A 0° C. solution of compound [1-(4-methoxy-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester (9.84 g, 33.7 mmol) in DMF (30 mL) was treated with sodium hydride (60% dispersion, 1.37 g, 34.3 mmol) and warmed to room temperature and stirred under N2 for 20 minutes. The resultant mixture was cooled to 0° C. and then treated with methyl iodide (6.16 g, 43.4 mmol) and then warmed to room temperature and stirred for 16 h. The reaction was quenched with aqueous 1 N HCl (60 mL) and then worked up extractively with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to give crude product that was purified by flash chromatography using 3:1 hexanes:actetone to afford 7.46 g (85%) [1-(4-methoxy-benzyl)-3-methyl-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester. MS (ES+) Calc'd for C15H19N2O5 (M+1) 307. Found m/z 307 (100%). 1H NMR.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1.[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](F)=[CH:15][CH:14]=1>>[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[CH:11]=[CH:10][S:9][C:5]2=3)=[CH:15][CH:14]=1
Reactant: Fc1ccc(Br)c2ccccc12
Reactant: CN1Cc2ccsc2C(O)C1
Product: CN1Cc2ccsc2C(Oc2ccc(Br)c3ccccc23)C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 14) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 1-bromo-4-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]([O:13][C:14]([N:16]1[C:24]2[C:19](=[C:20]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=3[F:38])[C:21]([N+:27]([O-])=O)=[C:22]([O:25][CH3:26])[CH:23]=2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1COCC1.C(=O)([O-])O.[Na+]>O.O1CCOCC1>[C:9]([O:13][C:14]([N:16]1[C:24]2[C:19](=[C:20]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=3[F:38])[C:21]([NH2:27])=[C:22]([O:25][CH3:26])[CH:23]=2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1cc2c(cnn2C(=O)OC(C)(C)C)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cnn2C(=O)OC(C)(C)C)c(Nc2ccc(I)cc2F)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
A suspension of sodium dithionite (524 mg, 3.48 mmol) and 4-(2-fluoro-4-iodo-phenylamino)-6-methoxy-5-nitro-indazole-1-carboxylic acid tert-butyl ester (434 mg, 0.87 mmol) in water (10 mL) was treated with a 1:1 mixture of THF:dioxane (10 mL). The homogeneous reaction mixture stirred at room temperature for 18 hours. The reaction mixture was basified by the addition of saturated aqueous sodium hydrogen carbonate and then extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a yellow solid (300 mg, 73%). LCMS (Method B) RT 4.16 min, [M+H]+=499 [M−H]−=497.
Reaction SMILES: [C:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[O:9][C@@H:8]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:33][O:34][C:35]1[C:43]([O:44][CH3:45])=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>O1CCOCC1>[CH3:33][O:34][C:35]1[C:43]([O:44][CH3:45])=[CH:42][CH:41]=[CH:40][C:36]=1[C:37]([N:20]1[C:21](=[O:22])[C:23]([F:25])=[CH:24][N:17]([C@@H:8]2[O:9][C@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[C@@H:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH2:7]2)[C:18]1=[O:19])=[O:38]
Reactant: COc1cccc(C(=O)Cl)c1OC
Reactant: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3cccc(OC)c3OC)c2=O)C[C@@H]1OC(=O)CC
Reaction time: 0.5 h
Yield: 79 %

Procedure:
2.0 Grams of 2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 2.2 g of 2,3-dimethoxybenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 30 minutes and then at 50° C. for 30 minutes. The reaction liquid is cooled and then triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (elution solvent: chloroform). The purified oily substance is allowed to stand overnight at room temperature whereby a part of the substance is crystallized. A small amount of ethanol is added to crystallize the substance wholly and the crystals are collected by filtration whereby 2.3 g (yield: 79.0%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are obtained. M.P. 84.5°-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][CH:12]([F:14])[F:13])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4].[Li+].[OH-].Cl.BrC[C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:28].C(N(CC)CC)C>CO>[C:18]([O:17][C:15]([N:6]1[CH2:7][CH:8]([CH2:10][O:11][CH:12]([F:14])[F:13])[CH2:9][CH:5]1[C:3]([O:2][CH2:1][C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:28])=[O:4])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1CC(COC(F)F)CN1C(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(COC(F)F)CC1C(=O)OCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.6 %

Procedure:
4-Difluoromethoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (398 mg, 1.29 mmol) was dissolved in MeOH (8 mL) and LiOH (1 M in H2O, 2 mL, 2 mmol) was added. After stirring at RT for 5 h, the MeOH was removed under reduced pressure. The aqueous solution was poured into a separatory funnel, diluted with 1 M HCl (2 mL, 2 mmol) and extracted with DCM (3×). The combined organics were dried over MgSO4, filtered and concentrated. The residue was dissolved in MeCN (4 mL) and treated with 2,4′-dibromoacetophenone (200 mg, 0.719 mmol), and triethylamine (0.100 mL, 0.719 mmol). After stirring for 15 h, the solvent was removed. The crude residue was purified by silica column chromatography (10% to 35% EtOAc/Hex) to afford the title compound (303 mg, 94%).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][N:7]([CH3:9])[CH2:6][CH2:5][N:4]1[C:10]1[N:15]=[CH:14][C:13]([S:16][CH3:17])=[C:12]([Cl:18])[N:11]=1.O.[CH2:20]([OH:23])[CH2:21][CH3:22]>[OH-].[K+]>[ClH:18].[CH3:1][NH:2][CH:3]1[CH2:8][N:7]([CH3:9])[CH2:6][CH2:5][N:4]1[C:10]1[N:15]=[CH:14][C:13]([S:16][CH3:17])=[C:12]([O:23][CH2:20][CH2:21][CH3:22])[N:11]=1
Reactant: CNC1CN(C)CCN1c1ncc(SC)c(Cl)n1
Reactant: CCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCOc1nc(N2CCN(C)CC2NC)ncc1SC
Product: Cl
Reaction time: 2 h

Procedure:
20 parts of 2-methylamino-4-N-methylpiperazino-5-methylthio-6-chloro-pyrimidine are dissolved in 130 parts by volume of n-propanol in the presence of 7 parts of caustic potash in pellets. The mixture is held for 2 hours at the reflux temperature, then poured into water. The oil which separates is extracted with ether. The organic phase is washed with water, dried and evaporated. The residue is taken up in petrol ether in which it solidifies. It is recrystallised from the petrol ether. M.p. 90° C.