Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[S:16][C:17]([CH3:20])=[N:18][N:19]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]2[N:32]([CH3:33])[C:31](=[O:34])[O:30][CH2:29][CH2:28][C:27]=2[CH:35]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[S:16][C:17]([CH3:20])=[N:18][N:19]=2)=[N:7][C:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]3[N:32]([CH3:33])[C:31](=[O:34])[O:30][CH2:29][CH2:28][C:27]=3[CH:35]=2)=[N:3][CH:4]=1
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Reactant: Cc1nnc(-c2ccccc2Nc2nc(Cl)ncc2Cl)s1
Product: Cc1nnc(-c2ccccc2Nc2nc(Nc3ccc4c(c3)CCOC(=O)N4C)ncc2Cl)s1

Procedure:
The title compound was prepared by combining (2,5-dichloro-pyrimidin-4-yl)-[2-(5-methyl-[1,3,4]thiadiazol-2-yl)-phenyl]-amine (Example N?, 75 mg, 0.22 mmol) and 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (Example N?, 47 mg, 0.24 mmol) in an analogous manner described in Example 356c. The title product was isolated as described in Example 1477b as a white powder (32 mg, 26%) and had the following properties: m.p: 174-177° C.; LC/MS (m/e): 494 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 10.75 (s, 1H), 9.40 (s, 1H), 8.40-5.06 (series of m, 2H), 8.04 (d, J=7.0, 1H), 7.75-7.30 (series of m, 4H), 7.10 (d, J=8.6, 1H), 4.30 (t, J=6.3, 2H), 3.23 (s, 3H), 2.37 (s, 3H), 2.60 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([CH3:19])[CH:3]=1.IC.[C:22](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:22])[CH:17]=2)=[O:11])=[C:4]([CH3:19])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)ccc1/C=C/C(=O)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CI
Product: Cc1cc(Cl)ccc1/C=C/C(=O)c1ccc(=O)n(C)c1

Procedure:
In analogy to example 161, step 1, 5-[(E)-3-(4-chloro-2-methyl-phenyl)-acryloyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow solid, MS (ESI+): m/z=288.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: Brc1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a stirred solution of 4-bromobiphenyl (50 g, 0.21 mol) in chloroform (200 mL) was added dropwise at room temperature chlorosulfonic acid (32.5 g, 0.28 mol). The solution was stirred at room temperature for 16 hours, then diluted with hexanes (200 mL). The precipitate was collected by filtration and washed with hexanes to give 4'-bromobiphenyl-4-sulfonic acid (52.3 g, 79%) as a white solid. The crude product was used in the next step without further characterization.
Reaction SMILES: [CH:1]1([C:4]2[N:5](COCC[Si](C)(C)C)[N:6]=[C:7]3[C:12]=2[CH:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[C:8]3[CH2:17][O:18][CH2:19][C:20]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH:1]1([C:4]2[C:12]3[C:7](=[C:8]([CH2:17][O:18][CH2:19][C:20]4([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)[CH:9]=[C:10]([C:13]([F:15])([F:14])[F:16])[CH:11]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3c(C4CC4)n(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCNCC2)c2[nH]nc(C3CC3)c2c1

Procedure:
tert-Butyl 4-(((3-cyclopropyl-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (18 mg, 0.03 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 4 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated to afford 9 mg (77%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.92 (s, 1H), 7.31-7.45 (m, 5H), 7.22-7.33 (m, 1H), 4.67 (s, 2H), 3.52 (s, 2H), 2.95-2.99 (m, 2H), 2.76-2.81 (m, 2H), 2.15-2.24 (m, 3H), 1.89-1.95 (m, 2H), 1.04-1.02 (m, 4H). Mass spec.: 430.16 (MH)+. Accurate mass spec.: m/z 430.2097 [MH]+, Δ=2.1 ppm.
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH2:12]Br>C(O)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH:12]=[O:3]
Reactant: CC(C)[N+](=O)[O-]
Reactant: Cc1cc(Cl)cc(CBr)c1
Agent: [Na]
Solvent: CCO
Product: Cc1cc(Cl)cc(C=O)c1
Reaction time: 3 h
Yield: 42.2 %

Procedure:
To a solution of sodium metal (52 mg, 2.3 mmol) in ethanol was added 2-nitropropane (0.23 g, 2.4 mmole) followed by the addition of 3-chloro-5-methybenzylbromide (0.5 g, 2.3 mmol). The reaction was allowed to stir for 3 hours and the precipitate formed was filtered off. The filtrate was concentrated under reduced pressure, redissolved in diethylether and washed with 1N sodium hydroxide (twice), water, and dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography using 10% dichloromethane and 90% petroleum ether, to give 0.15 g of 3-chloro-5-methylbenzaldehyde. 1H-NMR (CDCl3): 2.46 (s, 3H) 7.43 (s, 1H) 7.56 (s, 1H) 7.68 (s, 1H), 9.92 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].[CH3:11][C:12]([CH3:14])=O.O>Br.C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:12]([CH3:14])[CH3:11])=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(C)=O
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)[nH]c(C(C)C)c1C
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Anhydrous stannous bromide (5g) was stirred to solution in 20 ml of hydrogen bromide in acetic acid (30-32 %). 2,4-Dimethyl-3-acetyl-pyrrole (548 mg) was added and the mixture was warmed to dissolve this, then cooled to 30° C. Acetone(0.6 ml) was added and the solution was stirred at 35° C. for 21/2 hrs then poured into water at 10° C. The product was separated and washed with dilute hydrochloric acid then with water. It formed colourless micro-prisms (549 mg. 77%), m.p. 166°-167° C. or 173-174.5° C. after changing to cubes at about 136° C. For analysis it was recrystallized from aqueous ethanol as prismatic rods, m.p. 172° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]([NH2:16])=[S:15]>CCO>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:14]([NH2:16])[S:15][CH:2]=2)=[CH:6][CH:7]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: COc1ccc(-c2csc(N)n2)cc1
Yield: 116.5 %

Procedure:
A mixture of 2-bromo-1-(4-methoxyphenyl)ethanone (5.00 g, 21.8 mmol) and thiourea (1.72 g, 22.6 mmol) in 95% EtOH (40 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-methoxyphenyl)thiazol-2-amine (5.24 g) as yellow solids in >99% yield: 1H NMR (500 MHz, DMSO-d6) δ 7.72 (d, 2H), 6.99 (s, 2H), 6.92-6.91 (m, 2H), 6.82 (s, 1H), 3.76 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:30][N:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([N:34]4[CH2:35][CH2:36][CH2:37][N:31]([CH3:30])[CH2:32][CH2:33]4)=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: CN1CCCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: CN1CCCN(c2ccc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cn2)CC1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-(4-methyl-[1,4]-diazepan-1-yl)-nicotinamide was prepared starting from intermediate E and N-methylhomopiperazine. MS calcd. for C28H28ClN5O2 [(M+H)+] 502.2, obsd. 502.0.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C([O-])([O-])=[O:33].[Na+].[Na+].O>OS(O)(=O)=O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH:23]5[CH2:24][N:25]([C:27]([CH3:31])([CH3:30])[C:28]([NH2:29])=[O:33])[CH2:26]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(C)(C)C#N)C3)cc1OCC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(C)(C)C(N)=O)C3)cc1OCC2
Reaction time: 3.25 h
Yield: 54 %

Procedure:
2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile (0.17 g, 0.41 mmol) was dissolved in conc. H2SO4, (2 mL) and the mixture allowed to stand at room temperature for 3.25 hr before adding to ice. The resultant solution was basified with Na2CO3, further water added, and the mixture extracted with 10% MeOH in DCM. The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 205 as a white solid (97 mg, 54%). 1H NMR δ (ppm) (CDCl3): 8.46 (1 H, d, J=8.29 Hz), 7.84 (1 H, s), 7.61 (1 H, s), 7.13 (1 H, s), 7.08 (1 H, d, J=8.39 Hz), 6.95 (1 H, s), 6.01-5.91 (1 H, m), 5.27 (1 H, s), 4.50-4.40 (4 H, m), 3.62 (3 H, s), 3.33 (2 H, s), 1.56 (6 H, d, J=6.63 Hz), 1.23 (6 H, s). LCMS: RT=2.53 min, M+H+=436
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH2:13](Br)[CH:14]=[CH2:15]>[OH-].[K+]>[CH2:15]([O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [K+]
Agent: [OH-]
Product: C=CCOc1ccc2cc(Br)ccc2c1

Procedure:
In reaction D, 6-bromo-2-naphthol and allylbromide, represented by the graphic formulae VIII and XIII, respectively, are refluxed together in ethanoic potassium hydroxide to produce 2-allyloxy-6-bromonaphthalene of graphic formula XIV. 2-Allyloxy-6-bromonaphthalene undergoes a Claisen rearrangement under high temperatures followed by acid catalyzed ring closure to produce 7-bromo-1,2-dihydro-2-methylnaphtho[2,1-b]furan of graphic formula XV. See Organic Reaction Vol. II, 1944, pages 1 to 48. The conversion of 7-bromo-1,2-dihydro-2-methylnaphtho[2,1-b]furan to 7-hydroxy-1,2-dihydro-2-methylnaphtho[2,1-b]furan represented by graphic formuale XVI is accomplished thru a series of steps described in Organic Synthesis Vol.49 pages 90-93, 1972. Other substituted 7-hydroxy-1,2-dihydronaphtho[2,1-b]furans may be synthesized by replacing allylbromide (XIII) with another reactant such as 3-bromo-2-methyl-propene. Coupling the resulting 7-hydroxy-1,2-dihydronaphtho[2,1-b]furan with the appropriate propargyl alcohol would result in compounds represented by graphic formula IB having formula IIB as group A. ##STR8##
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([O:37][CH3:38])[CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=2[O:37][CH3:38])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: COc1cc(F)ccc1-c1cncc(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluoro-2-methoxy-phenylboronic acid, 5-(4-fluoro-2-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of an off-white foam (yield=92%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][CH:5]=1.I[C:14]1[C:22]2[C:17](=[CH:18][C:19]([CH:23]=[O:24])=[CH:20][CH:21]=2)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:15]=1>>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:14]2[C:22]3[C:17](=[CH:18][C:19]([CH:23]=[O:24])=[CH:20][CH:21]=3)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:15]=2)=[CH:6][CH:5]=1)[CH3:12]
Reactant: C=Cc1ccc(CN(C)C)cc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Product: CN(C)Cc1ccc(/C=C/c2nn(COCC[Si](C)(C)C)c3cc(C=O)ccc23)cc1
Temperature: 90 °C

Procedure:
The title compound was synthesized according to the method of Example A22A, utilizing N,N-dimethyl-1-(4-vinylphenyl)methanamine (42 mg, 0.26 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (70 mg, 0.17 mmol) with heating in a sealed tube at 90° C. overnight instead of with microwave irradiation. Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a pale orange gum (33.4 mg, 44%). 1H NMR (400 MHz, CD3OD) δ ppm 10.13 (s, 1 H), 8.27 (m, 2 H), 7.81 (d, J=9.29 Hz, 1 H), 7.69 (d, J=8.28 Hz, 2 H), 7.61 (d, J=16.6 Hz, 1 H), 7.50 (d, J=16.6 Hz, 1 H), 7.43 (d, J=8.28 Hz, 2 H), 5.86 (s, 2 H), 3.82 (s, 2 H), 3.62 (t, J=8.03 Hz, 1 H), 2.50 (s, 6 H), 0.87 (t, J=8.03 Hz, 2 H), −0.09 (s, 9 H); MS ESI 436.3 [M+H]+, calcd for [C25H33N3O2Si+H]+ 436.6.
Reaction SMILES: [N:1]1([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([O:9][CH3:10])=[O:8].CI.[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:23][C:2]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][O:4][CH2:5][CH2:6][N:1]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: COC(=O)C1COCCN1C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)COCCN1C(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
4-Benzyl 3-methyl morpholine-3,4-dicarboxylate (13.98 g, 50.1 mmol) and methyl iodide (5.70 ml, 91 mmol) was dissolved in THF (100 ml). The solution was cooled to −70° C. A solution of NaHMDS in THF (1 M, 91 ml, 91 mmol) was added via syringe over 2 minutes. The reaction solution was stirred for 5 hours at −40 to −70° C. and then was quenched with MeOH (5 ml) and HOAc (3.5 g). The reaction mixture was concentrated. The residue was then partitioned between EtOAc (400 ml) and water (150 ml). The organic phase was separated. The aqueous phase (pH about 7) was extracted with EtOAc (100 ml). The combined organic phases were washed with water (100 ml). The organic solution was then concentrated to give an oil. The residue was purified by silica gel column (220 g silica gel, Hexane/EtOAc 5:1) to afford 11.6 g of 4-benzyl 3-methyl 3-methylmorpholine-3,4-dicarboxylate as an oil (79% yield). 1H NMR (400 MHz, CDCl3) δ=1.58 (s, 3H), 3.23-3.78 (m, 9H), 4.99 (m, 2H), 7.17-7.27 (m, 5H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](I)[C:3]=1[NH2:10].[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:8][C:6]1[CH:5]=[C:4]2[C:3](=[C:2]([Cl:1])[CH:7]=1)[NH:10][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:18]2
Reactant: Nc1c(Cl)cc(Cl)cc1I
Reactant: C#Cc1ccccc1
Product: Clc1cc(Cl)c2[nH]c(-c3ccccc3)cc2c1
Yield: 85 %

Procedure:
The general procedure was used to convert 2,4-Dichloro-6-iodo-phenylamine and phenylacetylene to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 85% yield. 1H NMR (300 MHz, DMSO) δ 11.82 (s, 1H), 8.01-7.98 (d, J=8.2, 2H), 7.57 (s, 1H), 7.51-7.46 (t, J=7.15, 2H), 7.40-7.36 (t, J=7.15, 1H), 7.26 (d, J=1.88, 1H), 6.95 (d, J=2.07, 1H). 13C NMR (75 MHz, DMSO) δ 141.99, 133.71, 131.98, 131.86, 129.60, 129.10, 126.98, 124.85, 121.56, 119.11, 117.40, 100.90. Anal. Calcd. for C14H9Cl2N: C, 64.15; H, 3.46; Cl, 27.05; N, 5.34. Found C, 64.09; H, 3.37; Cl, 27.05; N, 5.28. m.p.: 135.5-137.5° C.
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:37]([CH3:39])[CH3:38])[CH:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1>O1CCCC1.C(O)C.[Pd]>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:37]([CH3:39])[CH3:38])[CH:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:31])[CH3:32])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 12 h
Yield: 88.5 %

Procedure:
To a solution of 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (12.4 g) in tetrahydrofuran (100 mL) and ethanol (60 mL) was added 10% (w/w) palladium on carbon (1 g) and the suspension was placed under a hydrogen atmosphere (3.4 bar) and shaken for 12 h. The solution was filtered through diatomaceous earth to give an oil which crystallized from ether to provide 2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide as a white solid (8.7 g); MS: m/z=513(M+1).
Reaction SMILES: Cl.Cl[C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[NH:17]1[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:9][C:8]1[C:3]([N:17]2[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]2)=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Cc1cncnc1Cl
Reactant: NC(=O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cncnc1N1CCC(C(N)=O)CC1
Reaction time: 0.25 h
Yield: 25.2 %

Procedure:
To a solution of 5-methyl-4-chloropyrimidne hydrochloride 22 (75 mg, 0.45 mmol) in DMF (2 mL) was added triethylamine (0.63 mL, 4.5 mmol). After stirring for 15 min, a solution of isonipecotamide (64 mg, 0.50 mmol) in DMF (2 mL) was added and the mixture was stirred at r.t. for a further 20 h. The mixture was poured into a saturated solution of sodium hydrogen carbonate (50 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, gradient 98:2 to 9:1) to furnish the title compound as a white solid (25 mg, 25%), m.p. 182-184° C.; umax (CHCl3)/cm−1 3024, 1678, 1581, 1439, 1359, 1147, 948; m/z (ESI) C11H17N4O requires 221.1397, found [M+H]+ 221.1394.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][C:10]([CH3:12])=O.CC(O)=O.[BH3-]C#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH:10]([CH3:12])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Nc1cncc(Br)c1
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromopyridin-3-amine (XXV) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 μL, 4.02 mL). The pH was adjusted to 4 using HOAc and stirred for 30 min. NaCNBH3 (272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% hexane→90:10 hexane:EtOAc) to produce 5-bromo-N-isopropylpyridin-3-amine (XLVI) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.12 (d, J=6.3 Hz, 6H), 3.55-3.59 (m, 1H), 6.03 (d, J=7.9 Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J=2 Hz, 1H), 7.90 (d, J=2 Hz, 1H); ESIMS found C8H11BrN2 m/z 215 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:12][CH3:13])[CH:7]([Cl:8])[CH:6](OC)[NH:5][C:4]1=[O:11].[C:14]([O:17][C@@H:18]1[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@@H:21]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:20][C@H:19]1[N:32]1[C:41]2[N:40]=[CH:39][N:38]=[C:36]([NH2:37])[C:35]=2[N:34]=[CH:33]1)(=[O:16])[CH3:15]>CCCCCC.CC(C)=O>[C:14]([O:17][C@@H:18]1[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@@H:21]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:20][C@H:19]1[N:32]1[C:41]2[N:40]=[CH:39][N:38]=[C:36]([NH:37][CH:6]3[NH:5][C:4](=[O:11])[C:3]([O:2][CH3:1])([O:12][CH3:13])[CH:7]3[Cl:8])[C:35]=2[N:34]=[CH:33]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC1NC(=O)C(OC)(OC)C1Cl
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COC1(OC)C(=O)NC(Nc2ncnc3c2ncn3[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)C1Cl
Yield: 63.2 %

Procedure:
3,3,5-Trimethoxy-4-chloro-2-pyrrolidinone (500 mg) was evenly admixed with adenosine 2',3',5'-triacetate (940 mg) and the mixture was melted and reacted at 170° C. for 1 hour. The reaction mixture was subjected to silica gel column chromatography using hexane-acetone (1:1) as the eluent to obtain N6 -(2-oxo-3,3-dimethoxy-4-chloro-5-pyrrolidinyl)adenosine 2',3',5'-triacetate (860 mg). This product was dissolved in ammonia-saturated methanol (40 ml) and allowed to stand at 5° C. for 15 hours, at the end of which time the solvent was distilled off. The residue was washed with chloroform and the insolubles were subjected to silica gel column chromatography using chloroform-methanol (10:1) as the eluent. The active fractions were pooled and concentrated under reduced pressure to give N6 -(2-oxo-3,3-dimethoxy-4-chloro-5-pyrrolidinyl)adenosine (590 mg).