Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn]([N:14]=[N+:15]=[N-:16])(CCCC)CCCC)CCC.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([CH:39]=[C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:41]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=1)=[O:29])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:43]([O:42][C:40]1[CH:39]=[C:27]([CH:26]=[C:25]([O:24][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:41]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[NH:16][N:15]=[N:14][N:38]=2)=[CH:33][N:32]=1)=[O:29])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(-c2nnn[nH]2)cn1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
Tributyltin azide (156 μL, 0.57 mmol) was added to a suspension of 3,5-bis(benzyloxy)-N-(5-cyanopyridin-2-yl)benzamide (180 mg, 0.41 mmol) in toluene (3 mL). The mixture was heated at reflux for 16 hours. The suspension was cooled and partitioned between ethyl acetate and hydrochloric acid (1M). The organic layer was concentrated in vacuo and the residue was purified by MPLC on silica MPLC (eluting with 1% methanol/DCM to 15% methanol/DCM). The tetrazole was obtained as a colourless solid (113 mg, 57%). 1H NMR δ (d6-DMSO): 5.19 (4H, s); 6.88 (1H, s); 7.26-7.48 (12H, m); 8.40 (1H, d); 8.46 (1H, dd); 9.04 (1H, s); 11.13 (1H, br s); m/z (LCMS; ESI+) 479 (MH+).
Reaction SMILES: CC([NH:5][C:6]([C:8]1[N:9]=[CH:10][N:11]2[CH2:16][N:15]([CH3:17])[N:14]=[N:13][C:12]=12)=[O:7])(C)C.[OH:18]S(O)(=O)=O>>[CH3:17][N:15]1[C:16](=[O:18])[N:11]2[CH:10]=[N:9][C:8]([C:6]([NH2:5])=[O:7])=[C:12]2[N:13]=[N:14]1
Reactant: O=S(=O)(O)O
Reactant: CN1Cn2cnc(C(=O)NC(C)(C)C)c2N=N1
Product: Cn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl-Temozolomide 8 (4.01 g, 16.023 mmol) and conc. H2SO4 (8 mL) (Fisher Scientific) were placed into a 50 mL flask equipped with a stirrer bar. The mixture was stirred for 2 hours at room temperature and then slowly poured into ice-cold EtOH (160 mL). A white precipitate formed, which was collected by vacuum filtration and washed with ice-cold EtOH (10 mL). The solid was dried under vacuum (20 mm Hg, room temperature, 72 hours) to yield 2.63 g of 9 (13.546 mmol, 98.4% pure against a standard sample by HPLC analysis)
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:20].[Na+:21]>O.O1CCOCC1>[NH2:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:20])=[O:1].[Na+:21]
Reactant: [OH-]
Reactant: COc1ccccc1Oc1cccc2c1NC(=O)C2
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1Oc1cccc(CC(=O)[O-])c1N
Reaction time: 30 h
Yield: 49.6 %

Procedure:
A mixture of 2-oxo-7-(2-methoxyphenoxy)indoline (2.7 g) and sodium hydroxide (2.1 g) in water (30 ml) and dioxane (30 ml) was refluxed with stirring for 30 hrs. The reaction mixture was concentrated in vacuo, and the residue was dissolved in water and filtered. The filtrate was washed with diethyl ether, neutralized with 5% sulfuric acid and extracted with diethyl ether. The extract was washed with saline, dried over magnesium sulfate and then evaporated in vacuo. The residue was treated with an aqueous solution of sodium bicarbonate, and the resultant oily substance (3.0 g) was crystallized by treating with ethyl acetate to give crystalline sodium 2-[2-amino-3-(2-methoxyphenoxy)phenyl]acetate (1.55 g). mp 101°-103° C. I.R. (NaCl, Nujol): 3500, 3400, 1615, 1600, 1580, 1500, 1470, 1390, 1310, 1265, 1200 cm-1.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)C1C=CC=CC=1.ClCCl.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCCl>[OH:8][C:9]1[C:10]([CH:16]=[CH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C=Cc2ccccc2)n1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(O)c(C=Cc2ccccc2)n1
Temperature: 50 °C
Yield: 32.6 %

Procedure:
875 mg of 3-benzyloxy-6-methyl-2-styrylpyridine (Example 57a) was dissolved in 15 ml of 1,2-dichloroethane and 1.2 ml of a dichloromethane solution containing 1.0 mol of boron tribromide was added thereto in a nitrogen atmosphere, followed by heating under stirring at 50° C. in an oil bath over night. After cooling as it was, an aqueous saturated sodium bicarbonate solution was added thereto, and the mixture was extracted with 5% methanol/dichloromethane. The organic phase was further washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was vacuum-dried, to give 200 mg of the target compound.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-])=O)=[CH:8][C:7]=1[Cl:16].O.C(=O)(O)[O-].[Na+]>C(O)C.[Fe]>[Br:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[CH:8][C:7]=1[Cl:16]
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1Br
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(N)cc(Cl)c1Br
Temperature: 100 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Iron (2.34 g, 41.8 mmol) and acetic acid (0.80 mL, 14.0 mmol) were added to a mixed solution of 2-bromo-1-chloro-3-methyl-5-nitro-benzene (3.50 g, 14.0 mmol) in ethanol (15 mL)-water (31 mL) at room temperature. The mixture was stirred at 100° C. for one hour, and a saturated aqueous sodium bicarbonate solution was then added at 0° C. The mixture was filtered through celite, and the filtrate was washed with ethyl acetate and water. The filtrate was concentrated under reduced pressure. Ethyl acetate was then added, and the organic layer and the aqueous layer were separated. The aqueous layer was repeatedly extracted with ethyl acetate three times, and the organic layers were then dried over sodium sulfate. The resulting residue was concentrated under reduced pressure to give 4-bromo-3-chloro-5-methyl-phenylamine as a pale brown solid (3.01 g, 98%).
Reaction SMILES: C1([N:7]=[N:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:13]([O:21][CH3:22])=[CH:12][C:11]=2[C:23]#[N:24])C=CC=CC=1>C(O)C>[CH3:22][O:21][C:13]1[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:15][C:10]2[N:9]=[N:8][N:7]=[C:23]([NH:24][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:11]=2[CH:12]=1
Reactant: CCCCOc1cc(NN=Nc2ccccc2)c(C#N)cc1OC
Solvent: CCO
Product: CCCCOc1cc2nnnc(Nc3ccccc3)c2cc1OC
Yield: 158.7 %

Procedure:
1-phenyl-3-(2-cyan-4-methoxy-5-n-butoxyphenyl)triazene (0.154 g, 0.47 mmol) and 70% ethanol (30.0 mL) were added into a flask. The solution was heated and refluxed to react for 1 h, then was evaporated under reduced pressure to dryness. Acetic acid glacial (20.0 mL) was added and the solution was refluxed for 1 h, cooled, filtered and washed with water till colorless. The crude product was purified by recrystallization with anhydrous ethanol to yield 0.121 g of light brown solid product with a recovery rate of 78.6%.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[OH:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: OB(O)c1cncnc1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1

Procedure:
5-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 151.1, 59 mg, 0.136 mmol), pyrimidin-5-ylboronic acid (33.7 mg, 0.272 mmol), Pd(PPh3)2Cl2 (9.54 mg, 0.014 mmol) and Na2CO3 (57.6 mg, 0.544 mmol) were added to a MW vial and treated with a mixture of DME (576 μL), water (165 μL) and EtOH (82 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min, diluted with DME (3 mL) and treated with Si-Thiol (Silicycle, 1.44 mmol/g, 56.6 mg, 0.082 mmol). The RM was centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column DEAP, from 10% to 15% in 10 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=0.92 min, m/z=434.3 [M+H]+, m/z=432.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.71 (s, 3H) 3.44-3.52 (m, 2H) 3.53-3.60 (m, 2H) 4.68 (t, J=5.14 Hz, 1H) 7.36 (d, J=8.41 Hz, 2H) 7.82-7.90 (m, 2H) 8.15 (d, J=2.38 Hz, 1H) 8.77 (d, J=2.38 Hz, 1H) 8.97 (s, 2H) 9.19 (s, 1H) 10.23 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[Cu][C:12]#[N:13].CN(C)C=O>O>[F:10][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[C:5]=1[OH:9])[C:12]#[N:13]
Reactant: N#C[Cu]
Reactant: Oc1c(F)cc(Br)cc1F
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(O)c(F)c1
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of 4-bromo-2,6-difluorophenol (4.00 g, 19.0 mmol), copper (I) cyanide (1.72 g, 19.0 mmol), and dimethylformamide (40 mL) was refluxed for 6 hours, cooled to room temperature, diluted with water (150 mL), and filtered. The tan solids obtained were washed with water and retained. The combined filtrates were acidified (1N HCl) and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (Silica Gel 60, 20% ethyl acetate in hexanes) to give 1.03 g of pure title compound as an off-white solid, mp 195°-197° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][CH2:22][CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:27]=[CH:26][C:25]([O:24][CH2:23][CH2:22][F:21])=[CH:32][CH:31]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(OCCF)cc1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OCCF)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 4-(2-fluoroethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 388.05 g/mol.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[C:14]=2[C:15]#[N:16])=[C:6]([CH2:26][CH2:27][CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2].C1CCCCC=1>C(O)C.[Pd]>[NH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:24]=[CH:25][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:29])[C:6]=2[CH2:26][CH2:27][CH3:28])[C:14]=1[C:15]#[N:16]
Reactant: CCCc1c(OCCCOc2cccc([N+](=O)[O-])c2C#N)ccc(C(C)=O)c1O
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCCc1c(OCCCOc2cccc(N)c2C#N)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
2.5 g of 10% palladium-on-carbon are added to a solution of 10 g (25.1 mmol) of 2-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propoxy]-6-nitrobenzonitrile and 10 g of cyclohexene in 500 ml of ethanol and the whole is heated under reflux for 30 minutes. After cooling to room temperature the mixture is filtered and freed of solvent. Ether is added to the residue and the crystals that have separated out are filtered off. 2-amino-6-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-benzonitrile having a melting point of 120°-122° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH:11](Br)[CH3:12])[CH:5]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:19]=[C:16]([CH3:17])[S:18][C:11]=2[CH3:12])[CH:5]=1
Reactant: CC(N)=S
Reactant: COC(=O)c1cccc(C(=O)C(C)Br)c1
Product: COC(=O)c1cccc(-c2nc(C)sc2C)c1
Temperature: 130 °C
Yield: 80.4 %

Procedure:
A mixture of rac-3-(2-bromo-propionyl)-benzoic acid methyl ester (6.78 g) and thioacetamide (5.63 g) was heated to 130° C. for 20 min. The mixture was partitioned between AcOEt and H2O, the organic layer was dried and evaporated and the residual oil was chromatographed on silica gel using AcOEt/hexane (1:4) as eluent to give 3-(2,5-dimethyl-thiazol-4-yl)-benzoic acid methyl ester (4.97 g) as yellow oil.
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]([C:9]2[NH:10][N:11]=[CH:12][CH:13]=2)=[N:2]1.[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.CN(C=O)C>O>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:6]([C:5]3[NH:1][N:2]=[C:3]([C:9]4[NH:10][N:11]=[CH:12][CH:13]=4)[CH:4]=3)=[O:8])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: O=C(O)c1cc(-c2ccn[nH]2)n[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2ccn[nH]2)n[nH]1
Yield: 15.6 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 1H,2′H-3,3′-bipyrazole-5-carboxylic acid (2.245 mmol, 0.4 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.871 mmol, 0.521 g) and using DMF (10 ml) as the solvent. Water was added to the reaction mixture and the mixture was extracted with EtOAc. The organic phase was washed with 2M Na2CO3, water and brine. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 0.1277 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.19 (d, 3H), 4.27-4.56 (m, 3H), 6.64 (bs, 1H), 6.84 (bs, 1H), 6.98 (d, 1H), 7.77 (bs, 1H), 7.81-7.87 (m, 2H), 7.93-7.6 (m, 1H), 8.07 (br. s, 1H), 12.57-13.78 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[N:7]([CH:17]=1)[C@@H:8]1[O:16][C@H:12]([CH2:13][NH:14][CH3:15])[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28](Cl)=[O:29].S(Cl)(Cl)=O>N1C=CC=CC=1.C1C=CC=CC=1.C(Cl)Cl.CO>[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28]([N:14]([CH2:13][C@H:12]1[O:16][C@@H:8]([N:7]2[CH:17]=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH2:9][C@@H:10]1[OH:11])[CH3:15])=[O:29]
Reactant: O=C(Cl)Cc1ccccc1Br
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC)O2)c(=O)[nH]c1=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CN(C)C(=O)Cc3ccccc3Br)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.72 g of 2',5'-dideoxy-5-ethyl-5'-methylaminouridine in 25 ml of dry pyridine was stirred at 0° C. and treated with a solution of (2-bromophenyl)acetyl chloride (prepared from 0.65 g of the acid by treatment with thionyl chloride in benzene under reflux) in 7 ml of benzene. The mixture was stirred at 0° C. for 0.5 hour and then stored at 4° C. overnight. The solvents were removed by evaporation and the residue was re-evaporated with toluene to give a gum which was subsequently triturated with diethyl ether to yield a solid. This solid was taken up in 5 ml of methylene chloride/methanol (9:1) and chromatographed on a column of silica gel using methylene chloride/methanol (9:1) for the elution. The fractions containing the product were combined and evaporated. The residue was re-evaporated with ethanol and recrystallized from methanol to give 0.18 g of 5'-[2-(2-bromophenyl)-N-methylacetamido]-2',5'-dideoxy-5-ethyluridine of melting point 182°- 185° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[NH:5][C:6]2[NH:7][CH2:8][CH:9]([CH:15]([OH:19])[CH:16]([OH:18])[CH3:17])[NH:10][C:11]=2[C:12](=[O:14])[N:13]=1.C(O[C:24](=[O:26])[CH3:25])(=O)C>C(O)(=O)C>[C:12]([O:18][CH:16]([CH3:17])[CH:15]([O:19][C:24](=[O:26])[CH3:25])[CH:9]1[CH2:8][NH:7][C:6]2[N:5]=[C:4]([NH2:3])[NH:13][C:12](=[O:14])[C:11]=2[N:10]1[C:16](=[O:18])[CH3:15])(=[O:14])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)OC(C)C(OC(C)=O)C1CNc2nc(N)[nH]c(=O)c2N1C(C)=O
Yield: 163.3 %

Procedure:
2-Amino-6-(1,2-dihydroxy-propyl)-5,6,7,8-tetrahydro-1H-pteridin-4-one dihydrochloride (0.1 g, 0.32 mmol) was slurried in acetic acid (3 ml). Acetic anhydride (300 uL, 3.2 mmol) was added and the mixture heated to reflux for 12 h. The reaction was concentrated and the crude material was purified by preparative RP-HPLC to give the final product as a white solid (0.096 g, 82%). 1H NMR (CD3OD) δ 5.15 (dd, J=2.4 Hz, J=10 Hz, 1H), 4.95-4.90 (m, 1H), 3.36 (d, J=13.6 Hz, 1H), 3.22 (dd, J=4.4 Hz, J=13.2 Hz, 1H), 2.16 (s, 3H), 2.09 (s, 3H), 1.85 (s, 3H), 1.26 (d, J=6.4 Hz, 3H). MS: ESI (positive): 368 (M+H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]4[O:26][CH2:25][O:24][C:21]=4[CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(OC(N1CCNCC1)=O)(C)(C)C.[F:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]=C=O)=[CH:50][CH:49]=1>C(Cl)Cl.C(N(CC)CC)C>[F:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]5[O:26][CH2:25][O:24][C:21]=5[CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:50][CH:49]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc3cc4c(cc23)OCO4)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc4c(cc23)OCO4)CC1

Procedure:
4-Chloro-6,7-methylenedioxyquinoline [obtained from 3,4-methylendioxyaniline following the protocol of Krogstad et. al. (De, D., Byers L. D., Krogstad, D. J. J. Heterocyclic Chem. 1997, 34, 315; 1H NMR ([D]6-DMSO), δ 6.28 (s, 2H), 7.45 (s, 1H), 7.50 (s, 1H), 7.65 (d, 1H), 8.62 (d, 1H)) (0.50 g, 2.4 mmol) and 1-tert-butoxycarbonylpiperazine (1.8 g, 9.6 mmol) are reacted according to method A yielding 391 mg of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-6,7-methylenedioxy quinoline. After cleaving the Boc group with trifluoroacetic acid (1.5 mL) in CH2Cl2 (1.5 mL), the piperazine is treated with 4-fluorophenylisocyanate (86 μL) and triethylamine (0.245 mL) according to method C yielding the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:28])[C:12]([NH:15][CH2:16][C:17]2[CH:27]=[CH:26][C:20]3[N:21]=[C:22]([S:24][CH3:25])[S:23][C:19]=3[CH:18]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](OC(OCC)OCC)C>C(O)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[N:15]([CH2:16][C:17]3[CH:27]=[CH:26][C:20]4[N:21]=[C:22]([S:24][CH3:25])[S:23][C:19]=4[CH:18]=3)[CH:29]=[N:28][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc2ccc(CNc3ccc(OCc4ccccc4)cc3N)cc2s1
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: CSc1nc2ccc(Cn3cnc4cc(OCc5ccccc5)ccc43)cc2s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of 4-(benzyloxy)-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine (2.49 g, 6.1 mmol) from the previous step, triethylorthoformate (60 mL), and formic acid (1.22 g) was stirred at 90° C. for 2 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 50% EtOAc in petroleum ether to 100% EtOAc to afford 6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (1.6 g, 62%) as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.50 (s, 1H), 7.44-7.49 (m, 2H), 7.30-7.40 (m, 4H), 7.26 (m, 1H), 7.13 (d, J=9.0 Hz, 1H), 6.98 (m, 1H), 5.41 (s, 2H), 5.10 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 418 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:23]([C:24]([O:26]C)=[O:25])=[C:16]3[CH2:17][CH:18]([O:20][CH2:21][CH3:22])[O:19][C:15]3=[CH:14][CH:13]=2)[N:4]=1.[OH-].[Na+].O>CS(C)=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:23]([C:24]([OH:26])=[O:25])=[C:16]3[CH2:17][CH:18]([O:20][CH2:21][CH3:22])[O:19][C:15]3=[CH:14][CH:13]=2)[N:6]=1
Reactant: CCOC1Cc2c(ccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC1Cc2c(ccc(Oc3nc(OC)cc(OC)n3)c2C(=O)O)O1
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
While stirring 1.2 g of methyl 5-(4,6-dimethoxypyrimidin-2-yl)oxy-2-ethoxy-2,3-dihydrobenzofuran-4-carboxylate in 20 ml of dimethylsulfoxide at room temperature, 2 ml of a 2N sodium hydroxide aqueous solution was dropwise added thereto over a period of 10 minutes and then the mixture was further stirred for 15 hours. The mixture was poured into water and extracted with diethyl ether. Then, the aqueous layer was acidified with 10% hydrochloric acid, and precipitated crystals were extracted with ethyl acetate, and the organic layer was washed with water and then dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to obtain 1.0 g (yield: 87%) of the desired compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]3[O:20][CH2:21][O:22][C:15]=13)=[CH:10][C:9]([O:23][CH3:24])=[C:8]([OH:25])[CH:7]=2)#[N:2].[Br:26][CH2:27][CH2:28]O>>[Br:26][CH2:27][CH2:28][O:25][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]4[O:20][CH2:21][O:22][C:15]=34)=[C:3]([C:1]#[N:2])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:23][CH3:24]
Reactant: COc1cc2c(Nc3cccc4c3OCO4)c(C#N)cnc2cc1O
Reactant: OCCBr
Product: COc1cc2c(Nc3cccc4c3OCO4)c(C#N)cnc2cc1OCCBr
Yield: 82 %

Procedure:
Using an analogous procedure to that described in Example 8, 3-cyano-7-hydroxy-6-methoxy-4-(2,3-methylenedioxyanilino)quinoline was reacted with 2-bromoethanol to give the title compound in 82% yield; NMR Spectrum: (DMSOd6) 3.88 (t, 2H), 3.94 (s, 3H), 4.51 (t, 2H), 5.96 (s, 2H), 6.8-6.93 (m, 3H), 7.34 (s, 1H), 7.8 (s, 1H), 8.42 (s, 1), 9.53 (s, 1H); Mass Spectrum: M+H+ 444.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:13])=[N:5][C:6]([CH3:12])=[C:7]([C:9]([CH3:11])=[CH2:10])[CH:8]=1.[N-:14]=[N+:15]=[N-:16].[Na+].O.CCOC(C)=O>CN(C=O)C>[N:14]([CH2:2][C:3]1[C:4]([CH3:13])=[N:5][C:6]([CH3:12])=[C:7]([C:9]([CH3:11])=[CH2:10])[CH:8]=1)=[N+:15]=[N-:16]
Reactant: C=C(C)c1cc(CCl)c(C)nc1C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)c1cc(CN=[N+]=[N-])c(C)nc1C
Temperature: 70 °C

Procedure:
A mixture of 96.5 mg of the 3-(chloromethyl)-2,6-dimethyl-5-(prop-1-en-2-yl)pyridine and 86.8 mg (1.34 mmol) of NaN3 in 3 mL of DMF was heated at 70° C. for 4 h. Water and EtOAc were added, and the layers were separated. The organic layer was washed with H2O (2×) and then with brine. It was dried over Na2SO4, filtered, and concentrated to give the crude azide (3-(azidomethyl)-2,6-dimethyl-5-(prop-1-en-2-yl)pyridine) which was used without further purification.