Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH3:13])=[C:7]([OH:9])[CH:8]=1.C(N(CC)CC)C.[I:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[NH:27][C:26](=[O:33])/[C:25]/2=[CH:34]/OC.O>CN(C)C=O>[OH:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[O:10][CH2:11][CH2:12][CH3:13])[CH2:2][NH:1]/[CH:34]=[C:25]1\[C:26](=[O:33])[NH:27][C:28](=[O:32])[C:29]2[C:24]\1=[CH:23][C:22]([I:21])=[CH:31][CH:30]=2
Reactant: CCCOc1ccc(CN)cc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An amount of 5-(aminomethyl)-2-propoxyphenol) (60 mg, 0.33 mmol) is dissolved in N,N-dimethylformamide (2 mL). 0.137 m/(1.0 mmol) of triethylamine is added followed by 100 mg (0.30 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione. After the mixture is stirred at room temperature for 30 min, water (5 mL) is added and the reaction mixture is stirred for 60 min. The precipitate is filtered and washed several times with anhydrous ether. The crude solid is then purified by high performance liquid chromatography to give 54 mg of a white solid. MS (ESI) m/z 480.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:4]=1[C:5]#[N:6].FC(F)(F)C(O)=O.[I:20]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[I:20][C:8]1[C:9]([CH3:11])=[N:10][C:3]([O:2][CH3:1])=[C:4]([C:7]=1[CH3:12])[C:5]#[N:6]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1nc(C)cc(C)c1C#N
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(C)c(I)c(C)c1C#N
Temperature: 0 °C
Yield: 94 %

Procedure:
2-methoxy-4,6-dimethyl-nicotinonitrile (1.0 g, 6.166 mmol) was disolved in 30 mL of anhydrous methylene chloride and then added with 6 mL of trifluoro acetic acid and N-iodosuccinimide (2.2 g, 9.248 mmol) in this order while stirring at 0° C. under the nitrogen atmosphere and then stirred again at room temperature for about 4 hours. The mixture was added with 60 mL of a saturated solution of sodium carbonate and 60 mL of a saturated solution of Na2S2O3 and then extracted twice with 80 mL of methylene chloride. The resulting organic layer was dried with anhydrous sodium sulfate, and filtered. A silica gel column chromatography (5% EtOAc/Hexanes) was performed on the resulting residue and 1.67 g (94%) of 5-iodo-2-methoxy-4,6-dimethyl-nicotinonitrile was obtained in white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([NH:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]2)[N:14]=[CH:13]3)[CH2:3][CH2:2]1.[C:26](Cl)(=[O:28])[CH3:27].CCN(CC)CC.CO>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([NH:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]2)[N:14]=[CH:13]3)[CH2:5][CH2:6]1
Reactant: N[C@H]1CC[C@H](Nc2ncc3cccc(OC4CCOCC4)c3n2)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC[C@H](Nc2ncc3cccc(OC4CCOCC4)c3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-N-[8-(tetrahydro-2H-pyran-4-yloxy)quinazolin-2-yl]cyclohexane-1,4-diamine (0.3 g, 0.876 mmol) and acetyl chloride (0.0825 g, 1.05 mmol) in CH2Cl2 (10 mL) was added Et3N (0.106 g, 1.05 mmol). The resulting mixture was stirred at room temperature overnight. TLC (DCM:MeOH=10:1) showed the reaction was complete. CH2Cl2 (30 mL) was added to the solution. The solution was washed with H2O (3×20 mL) and brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give crude solid, which was washed with ethyl acetate to give the title compound (0.180 g, 54.5%) as a white solid. 1H NMR (CDCl3, 400 Hz): 8.875 (s, 1H), 7.255 (d, 2H), 7.132 (d, 1H), 7.050 (t, 1H), 5.245 (d, 1H), 5.133 (d, 1H), 4.002 (m, 2H), 3.869 (m, 1H), 3.709 (m, 1H), 3.507 (m, 2H), 2.178 (d, 2H), 1.979 (t, 4H), 1.893 (m, 5H), 1.249 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([N:27]1[CH2:30][CH:29](O)[CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(#N)C.CCOC(C)=O.CCCCCC>[CH:14]([N:27]1[CH2:30][CH:29]([O:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=2)[CH2:28]1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCCCC
Product: c1ccc(-c2ccc(OC3CN(C(c4ccccc4)c4ccccc4)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Phenylphenol (8.51 g, 50 mmol), 1-benzhydrylazetidin-3-ol (11.97 g, 50 mmol) and triphenylphosphine (13.11 g, 50 mmol) were stirred in acetonitrile (250 mL) for 20 minutes at room temperature, until all the reagents were fully dissolved. Diisopropyl Azodicarboxylate (9.84 mL, 10.11 g, 50 mmol) was added dropwise. A white precipitate forms and the initial reaction is mildly exothermic. The yellow colour is immediately discharged. After 5 minutes, the reaction is heated to reflux temperature, whereupon the precipitate dissolved, and stirred at this temperature for 3.25 hours. The mixture was cooled to room temperature, and scratched with a spatula to induce crystallisation. The mixture was cooled on ice, and the solids collected by filtration. The solids were washed with further cold acetonitrile and dried thoroughly to give the ether (15.42 g, 79%) as a white powder; mp 141-142° C.; Rf 0.68 (2:1 hexane:EtOAc); LCMS retention time 2.57 mins, m/z 392.2 [M+H]+; 1H nmr (400 MHz; DMSO-d6) δ 7.60-7.52 (m, 4H), 7.46-7.39 (m, 6H), 7.31-7.26 (m, 5H), 7.19 (tt, 2H, J=7.2 and 2.0 Hz), 6.90 (d, 2H, J=8.8 Hz), 4.88 (app qn, 1H, J=5.6 Hz), 4.53 (s, 1H), 3.67-3.63 (m, 2H) and 3.02-2.98 (m, 2H).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[N:10]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:11][C:12](=O)[NH:13]2.C(OP(Cl)(OCC)=O)C.[N+:35]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])#[C-:36]>C1COCC1>[F:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[N:10]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:11][C:12]1[N:13]2[CH:36]=[N:35][C:37]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]
Reactant: [C-]#[N+]CC(=O)OC(C)(C)C
Reactant: O=C1CN(C(=O)N2CCCC2)c2c(F)cccc2N1
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ncn2c1CN(C(=O)N1CCCC1)c1c(F)cccc1-2
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (1M, 3.8 ml) is added to 5-fluoro-1,2,3,4-tetrahydro-4-[(pyrrolidino)carbonyl]quinoxalin-2-one (XXXII, EXAMPLE 29, 0.908 g) at 0° in THF (20 ml). The mixture is stirred for 30 min and then diethylchlorophosphate (0.55 ml) is added. The reaction is stirred for 1 hr at 0°, then cooled at -78°. tert-butyl isocyanoacetate (0.58 g) is added, followed by potassium tert-butoxide (1 M, 4.14 ml). The reaction is stirred at -78° for 4 hr, then allowed to warm to 20°-25° over 1 hr. The mixture is then partitioned between ethyl acetate, water, and saline. The organic layers are dried over magnesium sulfate and concentrated. The crude product is chromatographed on silica gel (250 ml) eluting with a gradient of ethyl acetate/dichloromethane (20/80 to 40/60). The appropriate fractions are pooled, concentrated and crystallized from dichloromethane/hexane to give the title compound; mp 213.5-214.5°; MS (m/z) at 386; IR (mineral oil) 1689, 1677, 1217, 1363 and 1157 cm-1 ; NMR (CDCl3) 1.63, 1.88, 3.36, 5.08, 7.08, 7.20, 7.33 and 8.00 δ.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:39])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[C:33]([CH3:38])=[N:34][O:35][C:36]=3[CH3:37])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)(C)(C)C>O1CCOCC1>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:39])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[C:33]([CH3:38])=[N:34][O:35][C:36]=3[CH3:37])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1
Reactant: Cc1noc(C)c1-c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)c2)cc1
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3N)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.020 g [2-((E)-3-{1-[4-(3,5-dimethyl-isoxazol-4-yl)-benzenesulfonyl]-1H-pyrrol-3-yl}-allanoylamino)-phenyl]-carbamic acid tert-butyl ester with a little amount of dioxane and 3 ml 4M HCL in dioxane is stirred at ambient temperature for 1 h. The suspension is centrifuged. The title compound is dried in vacuo. By this method 0.013 g of a red-brown amorph substance are obtained.
Reaction SMILES: O=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1.[OH-].[Li+].[O:37]1CCCC1.O>CO>[O:37]=[C:18]1[O:17][C:16]2[CH:21]=[C:22]3[C:10]4([C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]([CH2:23][C:24]5[C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=5)[CH2:2]4)[CH2:11][O:12][C:13]3=[CH:14][C:15]=2[O:20][CH2:19]1
Reactant: CCOC(=O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1COc2cc3c(cc2O1)C1(CO3)CN(Cc2ncccc2C(=O)O)c2ccccc21
Temperature: 25 °C
Yield: 91 %

Procedure:
A 250 mL round-bottom flask was charged with ethyl 2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylate (2.3 g, 5.0 mmol), lithium hydroxide (0.48 g, 20.0 mmol), tetrahydrofuran (30.mL), water (50.mL) and methanol (30 mL). The reaction mixture was stirred under nitrogen at reflux for 5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was taken up in water (100 mL) and acidified to pH 1 by the addition of 10 M hydrochloric acid, causing a precipitate to be deposited. The solid was collected by filtration, washed with water and recrystallized from ethanol (50 mL) to afford 2-[(2-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylic acid (1.96 g, 91%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ8.57-8.45 (m, 1H), 8.33-8.26 (m, 1H), 7.42 (dd, J=7.82, 4.77 Hz, 1H), 7.21-6.83 (m, 4H), 6.49-6.44 (m, 2H), 5.39 (ABq, 2H), 4.72 (ABq, 2H), 4.24-4.00 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[NH:8][CH2:7][CH2:6]2.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[S:24][C:25]([S:28](Cl)(=[O:30])=[O:29])=[C:26]([CH3:27])[C:22]=2[CH:21]=1>>[Cl:19][C:20]1[CH:33]=[CH:32][C:23]2[S:24][C:25]([S:28]([N:8]3[C:9]4[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N:12]5[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]5)[CH:10]=4)[CH2:6][CH2:7]3)(=[O:29])=[O:30])=[C:26]([CH3:27])[C:22]=2[CH:21]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COc1cc2c(cc1N1CCN(C)CC1)NCC2
Product: COc1cc2c(cc1N1CCN(C)CC1)N(S(=O)(=O)c1sc3ccc(Cl)cc3c1C)CC2

Procedure:
The title compound (E124) was prepared from 5-methoxy-6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole (WO95/06637 intermediate 3) (99 mg, 0.4 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (113 mg, 0.4 mmol) using the method of Example 1 (194 mg, 92%) MH+=492/494.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:12](=O)([O-])[O-:13].[K+].[K+]>O>[OH:13][CH2:12][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Product: O=C(NCO)c1ccccc1
Temperature: 45 °C
Reaction time: 48 h

Procedure:
Benzamide (25 g, 206 mmol), formaldehyde (37% aqueous, 70 mL, 890 mmol), and potassium carbonate (700 mg, 5 mmol) were mixed in 36 mL of water. The mixture was heated at 45° C. long enough to dissolve the reagents and then cooled to room temperature. The reaction was allowed to proceed for 48 hours when 1H NMR indicated that the reaction was complete. The reaction was diluted with about 500 mL of water and crystals began to form and were allowed to continue to form for 18 hours. The crystals were collected by vacuum filtration, washed with water, and vacuum dried at 40° C. The filtrate was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and evaporated to give a white solid which was also vacuum dried at 40°C. The lots were combined for a total of 29.0 g of title compound. 93%. 1H NMR consistent with title compound.
Reaction SMILES: [Si]([C:8]1[O:9][C:10]2[C:30]([O:31][C:32](=[O:34])[CH3:33])=[C:29]([O:35][CH3:36])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)(C(C)(C)C)(C)C.[Br:37]Br>ClCCCl>[Br:37][C:8]1[O:9][C:10]2[C:30]([O:31][C:32](=[O:34])[CH3:33])=[C:29]([O:35][CH3:36])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1
Reactant: COc1cc(C(=O)c2c([Si](C)(C)C(C)(C)C)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: BrBr
Solvent: ClCCCl
Product: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 0.17 h
Yield: 43.2 %

Procedure:
To a stirred solution of 2-t-butyldimethylsilyl-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (120 mg, 0.44 mmol) in 1,2-dichloroethane (1 mL) at room temperature under nitrogen was added bromine (12 μl, 0.44 mmol) dropwise and the reaction mixture was stirred at this temperature for 10 minutes. After this time the reaction was quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate (20 mL), dried over magnesium sulfate and the solvent removed by distillation under vacuum. The crude product was purified by silica gel column chromatography (eluent=Hexane:diethyl ether; 8:2-7:3) to afford the title compound as a colourless crystalline solid (91 mg, 81%); 1H NMR (300 MHz, CDCl3) δ 7.40(d, 1H, J=8.70 Hz), 7.14(s, 2H, benzoyl-Hs), 6.98(d, 1H, J=8.75 Hz), 3.94(s, 3H, OMe), 3.89(s, 3H, OMe), 3.86(s, 6H, 2×OMe), 2.43(s, 3H); 13C NMR (75 MHz, CDCl3) δ 187.95(CO), 167.71, 152.75, 149.54, 147.49, 142.59, 131.92, 131.80, 123.91, 121.84, 119.89, 117.72, 109.89, 106.92, 60.69, 56.61, 56.00, 20.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=O)[CH3:11].[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:15][NH2:16]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH3:11]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COc1ccccc1CC(C)=O
Product: COc1ccccc1CC(C)NCC(O)c1cccc(Cl)c1

Procedure:
N-[2-(2-methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine, m.p. 85°-7° C. was prepared from 1-(2-methoxyphenyl)propan-2-one (2.69 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (2.81 g) as a 32:68 mixture of diastereoisomers, by an analogous procedure to that described in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[N:11]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([Br:24])[C:21]=1[O:22][CH3:23])[C:16](Cl)=[O:17].C(N(CC)CC)C.O>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([C:16]([N:10]2[CH2:9][CH2:8][O:7][C:6]3[N:11]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]2=3)=[O:17])[CH:19]=[C:20]([Br:24])[C:21]=1[O:22][CH3:23]
Reactant: Cc1ccc2c(n1)OCCN2
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3nc(C)ccc32)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 10 ml flask, 6-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (110 mg, 0.73 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (240 mg, 0.73 mmol) were dissolved in dichloromethane (5 ml). Triethylamine (0.26 ml, 1.8 mmol) was added thereto and then stirred at room temperature for 1 hour. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica (NH-silica gel) eluting with a solvent of dichloromethane:methanol=19:1. The fractions containing the product were collected and evaporated to obtain the target compound 58, i.e., (3,5-dibromo-4-methoxy-phenyl)-(6-methyl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone, as white solid (230 mg, 71%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.Br[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[N:21][CH:22]=1>>[CH3:23][C:20]1[N:21]=[CH:22][C:17]([CH2:16][O:1][C:2]2[CH:7]=[N:6][N:5]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][O:9]3)[C:4](=[O:14])[CH:3]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(CBr)cn1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Product: Cc1ccc(COc2cnn(C3CCCCO3)c(=O)c2)cn1
Yield: 43.6 %

Procedure:
5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.62 g, 13.4 mmol) and 5-(bromomethyl)-2-methylpyridine (7.47 g, 40.2 mmol) were reacted following the procedure for Example 17 (step a) to provide the title compound (1.76 g, 43%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.47 (s, 1H), 7.67 (d, J=6.2 Hz, 1H), 7.62-7.59 (dd, J=7.9, 2.3 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 6.19 (d, J=2.8 Hz, 1H), 6.03-5.99 (dd, J=10.5, 2.0 Hz, 1H), 4.97 (s, 2H), 4.15-4.08 (m, 1H), 3.78-3.69 (td, J=11.6, 2.6 Hz, 1H), 2.59 (s, 3H), 2.16-2.00 (m, 2H), 1.74-1.54 (m, 4H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10])(=[O:28])[CH3:27]
Reactant: C#CCN1CC[C@H](O)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCN1CC[C@H](OC(C)=O)C1=O
Reaction time: 3 h

Procedure:
A mixture of 5.0 g of (S)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 6.7 ml of pyridine, 0.2 g of dimethylaminopyridine and 6.7 ml of acetic anhydride was stirred in a water bath for 3 hours. The mixture was diluted with 150 ml of dichloromethane, washed in succesion with water, sodium bicarbonate solution, 1N hydrochloric acid, sodium bicarbonate solution and brine, dried and concentrated, giving 6.4 g of (S)-3-(acetyloxy)-1-(2-propynyl)-2-pyrrolidinone [α]D26° =-45° (dichloromethane).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].C(O[Cl:15])(C)(C)C>CO>[Cl:15][N:6]1[CH2:7][CH2:8][N:4]([CH2:3][CH2:2][OH:1])[C:5]1=[O:9]
Reactant: O=C1NCCN1CCO
Reactant: CC(C)(C)OCl
Solvent: CO
Product: O=C1N(Cl)CCN1CCO
Reaction time: 1.5 h
Yield: 60.3 %

Procedure:
A solution of 1-(2-hydroxyethyl)imidazolidin-2-one (418 mg, 3.2 mmol) in MeOH (6 ml) was cooled to 0° C. tert-Butylhypochlorite (450 ul, 4 mmol) was added. The resulting solution was stirred for 90 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (0 to 12% methanol in dichloromethane) to give a white solid (317 mg, 1.93 mmol, 60%). 1H NMR (400 MHz, D2O) δ 3.28-3.31 (t, J=5.3 Hz, 2H), 3.47-3.51 (m, 2H), 3.56-3.59 (m, 2H), 3.62-3.64 (t, J=5.3 Hz, 2H). 13C NMR (100 MHz, D2O) δ 43.31, 46.6, 51.9, 58.3, 163.9. LRMS (ESI/APCI) m/z 165 [M+H]+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:29]=[CH:28][C:27]([O:30][Si](C(C)(C)C)(C)C)=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH3:38])=[N:25]2>O1CCCC1.ClCCl>[Br:19][C:20]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH3:38])=[N:25]2
Reactant: Cc1ccc2c(Br)ccc(O[Si](C)(C)C(C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc2c(Br)ccc(O)c2n1
Reaction time: 0.17 h

Procedure:
Tetrabutylammonium fluoride (54 ml, 1M in tetrahydrofuran) was added dropwise to a stirred solution of 5-bromo-8-t-butyldimethylsilyloxyquinaldine (16.3 g) in tetrahydrofuran (500 ml). After stirring for 10 minutes the reaction was diluted with dichloromethane (500 ml) and extracted with water (3×200 ml). The organic phase was dried over magnesium sulphate and concentrated in vacuo. Purification by recrystallisation from aqueous methanol afforded the title compound as an off white solid (7.7 g).
Reaction SMILES: [CH3:1][C:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=2)[CH2:4][CH2:3]1.[I:15]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O>[CH2:13]([O:12][C:10]([C:7]1[C:6]([I:15])=[C:5]([C:2]2([CH3:1])[CH2:3][CH2:4]2)[O:9][N:8]=1)=[O:11])[CH3:14]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cc(C2(C)CC2)on1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1noc(C2(C)CC2)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
A mixture of ethyl 5-(1-methylcyclopropyl)isoxazole-3-carboxylate (Preparation 4C, 1.5 g, 7.68 mmol) and 1-iodopyrrolidine-2,5-dione (2.07 g, 9.22 mmol) in TFA (25 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed sequentially with water (50 mL), 1N aqueous sodium hydroxide (50 mL), 2.5 M aqueous sodium bisulfate (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give ethyl-4-iodo-5-(1-methylcyclopropyl)isoxazole-3-carboxylate (1.93 g, 75% yield) as a yellow liquid. The product had an HPLC ret. time=2.49 min. (condition B); LC/MS M+1=321.9; 1H NMR (400 MHz, CDCl3) δ ppm 0.85 (m, 2H), 1.12 (m, 2H), 1.40 (t, J=7.15 Hz, 3H), 1.42 (s, 3H), and 4.41 (q, J=7.15 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][CH2:20][CH2:19][O:18][CH3:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: COCCN
Solvent: CCN(CC)CC
Product: COCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(2-methoxyethylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-methoxyethylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1.Cl.[CH3:18][NH:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N:19]([CH3:20])[CH3:18])=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1
Reactant: CNC
Reactant: COC(=O)c1ccc(F)c(OC(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c(OC(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a stirred solution of 5.36 g (22.5 mmol) 14a and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 8 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 14b was obtained in 69% yield (4.09 g, 15.5 mmol).