Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[Cl:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]3[S:20][C:21]([NH2:23])=[CH:22][C:15]=23)=[CH:11][CH:10]=1.Cl>C(O)=O>[Cl:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]3[S:20][C:21]([NH:23][CH:1]=[O:3])=[CH:22][C:15]=23)=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Agent: Cl
Solvent: O=CO
Product: O=CNc1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Temperature: 70 °C
Reaction time: 96 h
Yield: 49 %

Procedure:
A mixture of 5 mL of acetic anhydride and 1.8 mL of 96% formic acid was heated to 70° C. for 3 hours. The solution was allowed to cool whereupon the obtained amine from Example 263 (32 mg, 0.12 mmol) was added. The mixture was stirred for 4 days and then poured into 50 mL of dilute HCl. The mixture was extracted with ethyl acetate, the combined extracts were washed with saturated sodium carbonate and then water, dried (MgSO4), and evaporated. Purification of the resulting product by preparative HPLC using a gradient of 30%-70% acetonitrile/water +0.1% TFA over 40 minutes afforded 18 mg (49%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH:4]1[CH2:8][S:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[N:5]1.[Br:21][CH2:22]CO.Cl.C([O-])(=O)C.C([NH+](CC)CC)C>O1CCOCC1>[Br:21][CH2:22][CH2:20][O:19][CH:3]([O:2][CH3:1])[CH:4]1[CH2:8][S:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[N:5]1
Reactant: COC(OC)C1CSC(c2nc3ccc(O)cc3s2)=N1
Reactant: OCCBr
Agent: CC(=O)[O-]
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: C1COCCO1
Product: COC(OCCBr)C1CSC(c2nc3ccc(O)cc3s2)=N1
Reaction time: 4 h

Procedure:
To a vial containing 2-(4-(dimethoxymethyl)-4,5-dihydrothiazol-2-yl)benzo[d]thiazol-6-ol (50 mg), 2-bromoethanol (1 mL) and a solution of HCl in dioxane (125 uL of 4M) was added. After 4 hours at room temperature, an aqueous solution of triethylammonium acetate (TEAA) (1 mL of 1M) was added to the reaction. After filtration, the solution was purified by preparative RP-HPLC by eluting with 50 mM TEAA ramping to acetonitrile over 30 min. Yield 26 mg. 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J=8.9, 1H), 7.33 (d, J=2.4, 1H), 7.06 (dd, J=2.3, 8.9, 1H), 4.88 (dt, J=6.8, 13.2, 1H), 4.79-4.67 (m, 1H), 4.16-3.73 (m, 3H), 3.64-3.38 (m, 8H), 1.36 (dd, J=2.4, 5.3, 1H). mass spectrum, calculated (MH+) 304/306. found 304/306
Reaction SMILES: [C@@H:1]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13](O)[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N+:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH:64]([NH2:66])[CH3:65])([O-:57])=[O:56]>CN(C=O)C>[N+:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH:64]([NH:66][C:13]1[C:12]2[N:11]=[CH:10][N:9]([C:18]=2[N:17]=[CH:16][N:15]=1)[C@@H:1]1[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1)[CH3:65])([O-:57])=[O:56]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Reactant: CC(N)c1ccccc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a suspension of 2′-deoxyinosine (100 mg, 0.4 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 210 mg, 0.48 mmol) in anhydrous DMF (1 mL), N,N-diisopropylethylamine (100 μL, 0.6 mmol) was added followed by the addition of a solution of 1-(2-nitrophenyl)ethylamine (250 mg, 1.51 mmol) in DMF (1 mL). The reaction was stirred at room temperature for 64 hours. Silica gel 60 (1 g, 60-200 mesh) was added, and the mixture was evaporated in vacuo to dryness. The residue was purified by silica gel column chromatography to yield N6-[1-(2-nitrophenyl)ethyl]-2′-deoxyadenosine dA.19 (67 mg, 42%, 1:1 mixture of diastereomers) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][C:13](=[O:18])[CH2:14][C:15](=[NH:17])[NH2:16])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:18])=[C:15]([NH2:16])[NH:17][C:15]=1[NH2:16])=[O:18])[CH3:11]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=Cc1ccccc1F
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1F
Yield: 49 %

Procedure:
Upon boiling a solution of 6.2 g 2-fluorobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 1 hour, 2,6-diamino-4-(2-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 128°-130° C (ethanol) is obtained.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:20][C:21](=[O:33])[CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:34][CH2:35][O:36]C)[CH:4]=[CH:5]2.[C:38](O)(=O)C>O>[C:35]([O:34][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][C:21](=[O:33])[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH2:11][CH2:10][C@@H:9]35)(=[O:36])[CH3:38]
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)CCCc4ccc(OC)cc4)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: CC(=O)O
Solvent: O
Product: COc1ccc(CCCC(=O)O[C@H]2CC[C@H]3[C@H]4Cc5ccc(OC(C)=O)c6c5[C@@]3(CCN4C)[C@H]2O6)cc1

Procedure:
4,5α-Epoxy-3-methoxymethoxy-6α-(4-(4-methoxyphenyl)-butyryloxy)-17-methyl-morphinane (0.85 g, 1.67 mmol) is dissolved in water (35 ml) and glacial acetic acid (35 ml) and then stirred for 4 hours at 100° C. The volatile components are eliminated using a Rotavapor. The residue thus obtained is purified by flash chromatography (100 g silica gel; mobile phase: methylene chloride/methanol=7:1). The product is dissolved in a mixture of water and glacial acetic acid and lyophilised.
Reaction SMILES: [F:1][CH:2]([C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:20].C(O)C.[Na]>C(O)(=O)C>[F:1][C:2](=[C:8]([NH2:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)C(=O)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(F)=C(N)c1ccccc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
6.0 g of ethyl a-fluorobenzoylacetate and 7.0 g of ammonium acetate were added to 50 ml of ethanol, followed by dropwise addition of 6.0 g of acetic acid to this solution with stirring at room temperature. The mixed solution was further stirred under reflux for 4 hours and added to a cooled aqueous solution of sodium hydrogencarbonte. This aqueous mixture was extracted with 200 ml of diethyl ether, and the organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was distilled away under reduced pressure to obtain 5.5 g of ethyl 2-fluoro-3-amino-3-phenyl-2-propenoate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:29][CH2:30][CH2:31][CH2:32][S:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:29][CH2:30][CH2:31][CH2:32][S:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[O:8])=[CH:2]1
Reactant: O=C(O)c1ccsc1
Reactant: NCCCSc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1ccsc1
Yield: 76 %

Procedure:
To a solution of 1.00 g (7.80 mmol) of thiophene-3-carboxylic acid and 1.08 g 410.1 mmol) of N-hydroxysuccinimide in 70 ml of methylene chloride, 1.80 g (9.36 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.31 g (7.80 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain 1.65 g of the desired compound (yield: 76.1%, colorless powder).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]([F:26])([F:25])[F:24])=[N:4][N:5]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[Br:27][CH2:1][C:2]1[C:3]([C:23]([F:26])([F:24])[F:25])=[N:4][N:5]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)cc2)c1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(CBr)c2-c2ccccc2)cc1

Procedure:
To a solution of 4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide prepared in Example 201 (500 mg, 1.3 mmol) in carbon tetrachloride (9 mL) and benzene (4 mL) was added N-bromosuccinimide (285 mg, 1.6 mmol). The mixture was irradiated with a sunlamp for 3.5 hours. The reaction mixture was partitioned between dichloromethane and water and the organic solution was dried and concentrated to give the desired product, 412 mg (69%).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH:10]([CH3:12])[N:9]2[C:4]3[C:5](=[CH:17][CH:18]=[CH:19][C:3]1=3)[C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8]2.S(=O)(=O)(O)O.[N+:25]([O-])([OH:27])=[O:26].[OH-].[NH4+]>>[OH:1][CH:2]1[CH2:11][CH:10]([CH3:12])[N:9]2[C:4]3[C:5](=[C:17]([N+:25]([O-:27])=[O:26])[CH:18]=[CH:19][C:3]1=3)[C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8]2
Reactant: O=[N+]([O-])O
Reactant: CC1CC(O)c2cccc3c(=O)c(C(=O)O)cn1c23
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC1CC(O)c2ccc([N+](=O)[O-])c3c(=O)c(C(=O)O)cn1c23
Reaction time: 24 h

Procedure:
A solution of 0.1 mole of 6,7-dihydro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in 150 ml. of concentrated sulfuric acid is treated with a mixture of 150 ml. of concentrated sulfuric acid and 10 ml. of nitric acid while keeping the temperature below 30° C. The solution is stirred for about 24 hours, poured over ice and partially neutralized to a pH of 2 with ammonium hydroxide. The product, 6,7-dihydro-7-hydroxy-5-methyl-10-nitro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid is isolated by filtration.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[C:10]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[C:9]1[CH3:33])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:26]([O:25][C:23]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[NH:8][C:9]=1[CH3:33])=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)c2cc(-c3cccnc3)ccc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1[nH]c2ccc(-c3cccnc3)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 134.1 %

Procedure:
2-Methyl-5-pyridin-3-yl-indole-1,3-dicarboxylic acid 3-benzyl ester 1-tert-butyl ester (0.027 g, 0.061 mmol, 1 eq) was suspended in dry CH2Cl2 (5 mL) under Ar. Trifluoroacetic acid (1.0 mL) was added, and the reaction mixture was stirred at room temperature. After 4 hours, the solvent was removed in vacuo, leaving 0.028 g (40% yield) of the indole-pyridine, a brown solid: LC/MS (ESI+) 343 (M+1), Anal.
Reaction SMILES: O.[NH:2]1[C:10](=[O:11])[C:8](=[O:9])[C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.Cl>C(O)C>[OH:9][C:8]1([C:14]2[N:13]([CH3:12])[CH:17]=[CH:16][CH:15]=2)[C:6](=[O:7])[NH:5][C:3](=[O:4])[NH:2][C:10]1=[O:11]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Cn1cccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1cccc1C1(O)C(=O)NC(=O)NC1=O
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Alloxan hydrate (3.2 g., 0.02 mole) was dissolved in 50 ml. of ethanol by warming. 1-Methylpyrrole (1.6 g., 0.02 mole) was added and the mixture warmed for 5 minutes on a steam bath, while perfusing with hydrogen chloride. After standing at room temperature for 0.5 hour, the reaction mixture was evaporated to dryness and the residue triturated with water to yield title product as a solid [2.9 g.; m/e 223; Rf 0.5 (1:1 ethyl acetate:hexane/5% acetic acid)].
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6](=[N:8][OH:9])[NH2:7])([O-:3])=[O:2].Cl[C:15](OCC)=[O:16]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]1[NH:7][C:15](=[O:16])[O:9][N:8]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cl
Reactant: NC(=NO)c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: O=c1[nH]c(-c2ccccc2[N+](=O)[O-])no1

Procedure:
The reactions of Equation 41 above can be run by methods known in the art. Thus, in reaction 41a, 2-nitrobenzamidoxime LII is reacted with ethyl chloroformate in excess pyridine at 0° to 100° C. for about 1 hour to form a 3-(2-nitrophenyl)-1,2,4-oxadiazolin-5-one of Formula (LIV), according to the teachings of A. R. Katritzky et al., Tetrahedron, 21, 1681 (1965). In reaction 41b, LIV is reacted with excess phosphorus oxychloride or phosphorus oxybromide with pyridine catalyst at 25° to 100° C. for 1 to 15 hours to form Xl'", according to the teachings of T. Fujita et al., Yakugaku Zasshi, 84, 1061 (1964). And in reaction 41c, Xl'" is reacted with sodium methoxide or sodium ethoxide in a solvent such as methanol, ethanol or tetrahydrofuran at 20° to 50° C. for about 0.2 to 1 hour to form Xl" ", according to the teachings of F. Eloy et al., Bull. Soc. Chim. Belg., 78, 47 (1969).
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=[N:2]1.S(=O)(=O)(O)O.[CH3:14][CH2:15]O>>[NH:1]1[C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][CH:3]=[N:2]1
Reactant: CCO
Reactant: O=C(O)c1ccn[nH]1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccn[nH]1
Temperature: 80 °C

Procedure:
To 1H-pyrazole-5-carboxylic acid (8.21 g, 73.2 mmol) in EtOH (100 mL) was added concentrated sulfuric acid (21.6 g, 220 mmol). The reaction mixture was heated to 80° C. for 16 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL) and 2N NaOH aqueous solution was added until pH=8. The phases were separated and the organic phase was washed with saturated NaHCO3 aqueous solution (50 mL) and brine (20 mL), dried (Na2SO4), and concentrated to give the product (6.36 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:10]C1C(=O)C(Br)=CC(Br)(Br)C=1.NC1C=CC=CC=1>C(Cl)Cl>[Br:10][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Reactant: COc1ccccc1N
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: COc1cc(Br)ccc1N
Temperature: 25 °C

Procedure:
2-Methoxyaniline (o-anisidine) (15 g, 0.122 mol) was brominated with 2,4,4,6-tetrabromo-2,5-cyclohexadienone (50 g, 0.122 mol) by dissolving the aniline in 250 ml of methylene chloride, chilling the solution to -10°, and slowly adding and brominating agent, keeping the temperature below -5°. The reaction was allowed to warm at room temperature, and then washed with 2N sodium hydroxide (2×75 ml), then washed with water (2×25 ml), dried over magnesium sulfate, and evaporated to dryness. The product was purified on a silica gel column, eluted with methylene chloride giving 23.68 g (96%) of the title compound, mp 56.5°-58° (petroleum ether). Anal. Calcd for C7H8BrNO: C, 41.61; H, 3.99; Br, 39.55; N, 6.93. Found: C, 41.59; H, 3.99; Br, 39.49; N, 6.92.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([O:15][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[C:18]([NH2:31])[N:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O>C(Cl)(Cl)Cl>[Br:1][C:21]1[N:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:23]2[C:19]([N:20]=1)=[C:18]([NH2:31])[N:17]=[C:16]([O:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)[N:24]=2
Reactant: Nc1nc(OC2CCCCC2)nc2c1ncn2C1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc(OC2CCCCC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
N-Bromosuccinimide (0.214 g, 1.2 mmol) was added to a stirred solution of 2-(cyclohexyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.254 g, 0.80 mmol) in chloroform (5 ml) at 0° C. The resultant mixture was stirred at 0° C. for 1.5 hours and then warmed to room temperature and stirred for a further 2 hours. Water (5 ml) was added and the phases separated using a hydrophobic frit. The organic phase was evaporated and the residue dissolved in dichloromethane and purified on a 70 g aminopropyl (NH2) cartridge eluting with a 0-100% ethyl acetate in cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (0.252 g).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=4[Cl:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(Cl)ccc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,5-dichloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=630.5)=60%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](Cl)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH2:16][CH2:15]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[O:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH2:18][CH2:19]1
Reactant: ClC(c1cccs1)c1cccs1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2cccs2)c2cccs2)CC1

Procedure:
The procedure of Example 36 (a) was repeated except for using di(2-thienyl)methyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-di(2-thienyl)methoxy-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: C[C:2]1(C)O[C:6](=[O:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([CH3:15])[O:3]1.C=[N:18][C:19]([CH3:31])([CH3:30])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C1(C)C(C)=CC=CC=1>[CH3:31][C:19]([N:18]1[C:6](=[O:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([CH3:15])[O:3][CH2:2]1)([CH3:30])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Reactant: C=NC(C)(C)C(=O)OCc1ccccc1
Solvent: Cc1ccccc1C
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)OCc2ccccc2)CO1
Yield: 90.2 %

Procedure:
To a mixture of 2,2,6-trimethyl-5-phenyl-4H-1,3-dioxin-4-one (13.97 g) and benzyl 2-(N-methylenamino)-2-methylpropionate (13.8 g) was added 130 ml of xylene, and the mixture was refluxed for 2 h. The solvent was evaporated and the residue was purified by chromatography on a silica gel column to get the captioned compound (21.1 g).
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:8][N:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[OH2:18].[OH-].[Li+]>C1COCC1.CO.O>[C:11]1([CH2:10][O:9][NH:7][CH2:8][C@@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([OH:17])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O
Reactant: CCCC[C@@H]1CN(OCc2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC[C@H](CNOCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of (3R)-3-butyl-1-[(phenylmethyl)oxy]-2-azetidinone (7) (52.8 g, 0.23 mol) in THF/MeOH (3:1, 1500 mL) at 0° C. was added Lithium hydroxide monohydrate (11.4 g, 0.27 mol) in water (375 mL). The mixture was warmed up to rt and stirred overnight. TLC indicated completion of the reaction. Organic solvents were removed under vacuum, and the aqueous solution was washed with DCM, acidified with 4 N HCl to pH ˜2.0, and extracted with DCM. The extracts were dried, filtered and concentrated to provide the title compound (40 g, 69%). LCMS: (M+H)+: 252.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]=[O:18])=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([Mg]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]([OH:18])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]([Br:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(C=O)c(Br)cc(OCc2ccccc2)c1=O
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1c(C(O)Cc2ccccc2)c(Br)cc(OCc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a 0° C. solution of 5-(benzyloxy)-3-bromo-1-methyl-6-oxo-1,6-dihydropyridine-2-carbaldehyde (1.09 g, 3.38 mmol) in 34 mL THF was added benzylmagnesium chloride (2.55 g, 3.38 mmol) dropwise. The mixture was allowed to stir at 0° C. for 1 h. After warming to room temperature, volatiles were removed under reduced pressure. The resulting residue was partitioned between dilute aqueous hydrochloric acid and ethyl acetate. The aqueous layer was removed and discarded, and the organic layer was collected, dried over anhydrous magnesium sulfate and purified by silica gel chromatography to afford 3-(benzyloxy)-5-bromo-6-(1-hydroxy-2-phenylethyl)-1-methylpyridin-2(1H)-one (1 g, 2.41 mmol, 71% yield). ES-MS (M+H)+=415.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][CH3:12])[N:3]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30](=[O:35])[CH2:29][N:7]1[C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][CH3:12])[N:3]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:2]1=[O:1]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCCOc1cc(=O)[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1cc(=O)n(CC(=O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To a mixture of 4′-[(2,4-dioxo-6-propoxy-3,4-dihydropyrimidin-1(2H)-yl)methyl]-biphenyl-2-carbonitrile (1 g), 1-bromo-3,3-dimethylbutan-2-one (0.59 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.17 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.8 g, 26%).