Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)([OH:3])=[O:2].[N+:13]([O-])([OH:15])=[O:14]>FC(F)(F)C(O)=O>[C:1]([C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To 5-carboxy-1,3-benzodioxole (50 g, 300 mmol) in trifluoroacetic acid (400 mL) at 0° C. was added HNO3 (38 mL, 900 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 hour, then warmed to ambient temperature and stirred for 3 hours. The mixture was poured into ice water and the resulting precipitate was collected by filtration. The solid was air dried overnight to afford 58 g (92% yield) of 5-carboxy-6-nitro-1,3-benzodioxole as a yellow solid; NMR (DMSO-d6) 7.6 (s, 1), 7.3 (s, 1), 6.3 (s, 2) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[ClH:13].Cl[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24]>C(O)(C)C.C(N(CC)CC)C>[Cl:13][CH:19]([NH:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:18]1[CH:21]=[CH:22][CH:15]=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: Clc1ccc2ncnc(Cl)c2c1
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc(C(Cl)Nc2ncnc3ccc(Cl)cc23)c1
Yield: 92.6 %

Procedure:
3.00 g (0.015 mol) of 4,6-dichloroquinazoline and 3.80 g (0.0170 mol) of 4-chloro-3-nitrobenzylamine hydrochloride were dissolved in a mixture comprising 100 ml of isopropyl alcohol and 15 ml of triethylamine. The obtained solution was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate) and recrystallized from chloroform/n-hexane to give 4.85 g of the title compound as a pale-yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[O:5][C:6]1[CH:7]=[C:8]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[NH:37][C:38](=[O:40])[CH3:39])[CH:9]=[CH:10][C:11]=1[CH:12]2[CH:17]1[CH2:23][CH:22]2[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:19]([CH2:20][CH2:21]2)[CH2:18]1.FC(F)(F)C(N1C2CCC1CC(C1C3C=CC(C4NN=NN=4)=CC=3OC3C1=CC=CC=3)C2)=[O:44]>>[CH:22]12[NH:24][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH:17]([CH:12]1[C:11]3[CH:10]=[CH:9][C:8]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[NH:37][C:38](=[O:40])[CH3:39])=[CH:7][C:6]=3[O:5][C:4]3[C:13]1=[CH:14][CH:15]=[CH:16][C:3]=3[O:2][CH3:1])[CH2:23]2.[C:25]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:44]
Reactant: COc1cccc2c1Oc1cc(-c3ccccc3NC(C)=O)ccc1C2C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: O=C(N1C2CCC1CC(C1c3ccccc3Oc3cc(-c4nnn[nH]4)ccc31)C2)C(F)(F)F
Product: COc1cccc2c1Oc1cc(-c3ccccc3NC(C)=O)ccc1C2C1CC2CCC(C1)N2
Product: O=C(O)C(F)(F)F

Procedure:
Using an adaptation of the method described in Procedure 23, substituting N-(2-{5-methoxy-9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-9H-xanthen-3-yl}-phenyl)-acetamide, 1l for 2,2,2-trifluoro-1-{3-[3-(1H-tetrazol-5-yl)-9H-xanthen-9-yl]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone, 4j, the title compound N-{2-[9-(8-aza-bicyclo[3.2.1]oct-3-yl)-5-methoxy-9H-xanthen-3-yl]-phenyl}-acetamide, 2l was obtained as a TFA salt. MS m/z (MH+) 455.1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C[Si]([C:28]#[N:29])(C)C>[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]2[C:28]#[N:29])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: c1ccc2ncccc2c1
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#CC1C=Cc2ccccc2N1C(=O)c1ccc(C(F)(F)F)cc1
Yield: 84.7 %

Procedure:
The title compound was prepared by the procedure described in step 1 of Example 1 using 13.0 g of quinoline, 32.0 g of 4-trifluoromethylbenzoyl chloride, 0.5 g of aluminum chloride, 14.8 g of trimethyl silyl cyanide, and 500 mL of methylene chloride. Crystallization from diethyl ether/hexane afforded the title compound (28.0 g) as a white solid, m. p. 149-151° C. This product was used for the preparation of the title compound described in step 2, and for preparation of the title compound described in Example 6.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][N:8]1[C:7]2=[O:21])[CH3:3].Cl[CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:24]([CH2:23][O:19][C:18]([C:16]1[CH:15]=[CH:14][C:9]2[N:8]([CH:17]=1)[C:7](=[O:21])[C:6]1[C:11](=[CH:12][CH:13]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=1)[N:10]=2)=[O:20])#[N:25]
Reactant: CC(C)c1ccc2nc3ccc(C(=O)O)cn3c(=O)c2c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc2nc3ccc(C(=O)OCC#N)cn3c(=O)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A suspension of 20 g of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, 6.3 ml of chloroacetonitrile and 13.2 g of potassium carbonate in 100 ml of dimethylformamide was stirred 18 hours at room temperature. The reaction mixture was diluted with 200 ml of water and the precipitated product collected to give 21.63 g (95%) of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid cyanomethyl ester, mp 186°-188° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:16][C:17]([OH:19])=O)[C:7]1=[O:20])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:45][C:46]1[C:47]([O:55][CH3:56])=[CH:48][C:49]([O:53][CH3:54])=[C:50]([NH2:52])[CH:51]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.Cl>[CH3:1][O:2][C:3](=[O:4])[CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:16][C:17](=[O:19])[NH:52][C:50]2[CH:51]=[C:46]([Cl:45])[C:47]([O:55][CH3:56])=[CH:48][C:49]=2[O:53][CH3:54])[C:7]1=[O:20]
Reactant: COC(=O)CN1Cc2ccccc2N(CC(=O)O)C1=O
Reactant: COc1cc(OC)c(Cl)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN1Cc2ccccc2N(CC(=O)Nc2cc(Cl)c(OC)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (3-methoxycarbonylmethyl-2-oxo-3,4-dihydro-2H-quinazolin-1-yl)-acetic acid (Intermediate J) (395 mg, 1.078 mmol), HATU (594 mg, 1.186 mmol) and 5-chloro-2,4-dimethoxy-phenylamine (293 mg, 1.186 mmol) in DCM (5 ml) is treated with DIPEA (2.5 eq, 618 μL). The reaction solution is stirred at RT and after 24 hours the reaction mixture is diluted with 1 M HCl (5 ml) and extracted with DCM (2×15 ml). The combined separated organic layers are washed with aqueous saturated NaHCO3. The organic phase is dried over MgSO4, filtered and is concentrated in vacuo to afford the title compound as off-white solid; [M+H]+ 448.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10](C=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.CO.[O:27]1[CH2:32][CH2:31][O:30][CH2:29]C1>>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([CH2:16][NH:15][C:32](=[O:27])[CH:31]([O:30][CH3:29])[C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:14][CH:13]=2)=[CH:18][CH:19]=1)#[N:22]
Reactant: N#Cc1ccc(CN)cc1
Reactant: C1COCCO1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Solvent: CO
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(N2CCOCC2)cc1

Procedure:
4-Morpholinobenzaldehyde was reacted according to general procedure A using methanol/dioxane as a solvent. The product of this reaction was subsequently coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-(4-morpholin-4-yl-phenyl)-acetamide. Orange oil. MS 366.2 ([M+H]+)
Reaction SMILES: ClC1C(N)=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1.C(O)=O.[Cl:18][C:19]1[C:27]2[NH:26][CH:25]=[N:24][C:23]=2[CH:22]=[C:21]([NH:28]C=O)[CH:20]=1.CCO>C(OC(=O)C)(=O)C.Cl.[Pd]>[Cl:18][C:19]1[C:27]2[NH:26][CH:25]=[N:24][C:23]=2[CH:22]=[C:21]([NH2:28])[CH:20]=1
Reactant: O=CNc1cc(Cl)c2[nH]cnc2c1
Agent: [Pd]
Agent: Cl
Agent: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCO
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(Cl)c2[nH]cnc2c1

Procedure:
Methanolic solution of 6-chloro-2,4-dinitroaniline (2.4 g, 11 mmol) was stirred overnight with 100 mg of 10% Pd/C under H2. Reaction mixture was filtered and concentrated in vacuo to provide an oil which was dissolved in 10 ml of acetic anhydride and 10 ml of formic acid and stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding a brown oil which was characterized as 4-chloro-6-foramidylbenzimidazole in NMR analysis. The foramide was dissolved in 20 ml of HCl sat'd EtOH and stirred for 3h at 25° C. The reaction mixture was purified in column chromatography (5% MeOH/EtOAc) to provide 0.89 g (5.3 mmol, 48% overall) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH3:12][O:13][C:14](=O)[O:15]C.[H-].[Na+].[CH3:20]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([CH3:20])([C:14]([O:13][CH3:12])=[O:15])[CH2:5]2
Reactant: CI
Reactant: COC(=O)OC
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(C)Cc2cc(Cl)ccc2C1=O
Temperature: 25 °C

Procedure:
To a mixture of 8.0 g of 5-chloroindanone and 4.2 ml of dimethylcarbonate in 60 ml of THF was added 4.0 g of 60% NaH and the mixture was heated to reflux under N2 overnight. After this time the reaction was cooled to room temperature and 4.0 ml of methyl iodide was added and the mixture was reheated to reflux overnight. The reaction was then cooled and partitioned between ether and 5% aqueous NaHCO3 and the aqueous extracts were washed twice with ether. The combined aqueous extracts were dried over MgSO4 and concentrated to 11.24 g of a brown oil. Chromatogrpahy on silica gel (10% ethyl acetate/hexane) afforded 4.25 g of the title compound as a brown oil. 1H NMR (CDCl3) δ 1.52 (s, 3H), 2.96 (d, 1H), 3.68 (s, 3H), 3.69 (d, 1H), 7.40 (d, 1H), 7.47 (s, 1H), 7.71 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14]C)=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:7]([O:20]C)[CH:6]=2.Br>C(O)(=O)C.O>[OH:20][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[C:3]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)=[N:4]2)=[CH:9][C:8]=1[S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(C)(=O)=O)cc12
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(C)(=O)=O)cc2c1C(=O)O
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A solution of methyl 3-methyl-7-(methyloxy)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (4.95 g, 10.92 mmol) and hydrobromic acid (30 mL, 552 mmol) in acetic acid (30 mL) was heated to reflux for 5 days. The mixture was cooled to room temperature and diluted with water. The solid precipitate was collected by filtration, washed with water, and air dried to afford 7-hydroxy-3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (4.22 g, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ14.51 (br. s., 1H), 11.77 (s, 1H), 8.32 (s, 1H), 7.95-8.00 (m, 2H), 7.90 (d, J=7.78 Hz, 1H), 7.78 (t, J=7.78 Hz, 1H), 7.54 (s, 1H), 3.41 (s, 3H), 2.36 (s, 3H); MS (m/z) 426.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOCC1CO
Temperature: -10 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (9.50 g, 41 mmol) was dissolved in anhydrous THF (50 mL) under nitrogen and cooled to −10° C. A 1M solution of borane (82 mL, 82 mmol) was added dropwise whilst maintaining the temperature below 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to −5° C. and water (10 mL) was added cautiously followed by Na2CO3 (9.5 g) in water (20 mL). After stirring for 30 min at room temperature the THF was removed in vacuo, water was added and the reaction mixture was extracted with diethylether (×3). The combined organic extracts were dried (MgSO4) and the solvent was evaporated in vacuo to give 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (8.9 g, 100%) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:31])[C:23]1[C:24](=[CH:26][CH:27]=[C:28]([I:30])[CH:29]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:24]=1[O:18][CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:19])[S:12][CH:13]=1
Reactant: COC(=O)c1cc(I)ccc1O
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)ccc1OCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (8.0 g) synthesized in Example 4 and 5-iodosalicylic acid methyl ester (7.3 g) were dissolved in tetrahydrofuran (130 mL), triphenylphosphine (9.0 g) and diethyl diazodicarboxylate (14.9 g) were added under ice-cooling, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (14.3 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([N:22]([CH3:24])[CH3:23])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([N:22]([CH3:23])[CH3:24])=[N:7][C:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=3)=[CH:19][CH:20]=2)=[N:9][C:10]=1[N:11]([CH3:12])[CH3:13]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(N)cc2)nc1N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc1N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of methyl[2-(4-aminobenzyl)-4,6-bis(dimethylamino)pyrimidin-5-yl]acetate (4.00 g, 11.65 mmol) in dichloromethane (120 mL) was treated with 4-trifluoromethylbenzoyl chloride (2.92 g, 13.98 mmol) and triethylamine (3.54 g, 34.94 mmol). After stirring for 1 hour at room temperature, the reaction mixture was partitioned between water and chloroform and the aqueous layer was extracted with chloroform. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product as a yellow colored solid which was recrystallized from methanol to give methyl[4,6-bis(dimethylamino)-2-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)pyrimidin-5-yl]acetate (4.34 g, 73%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([CH3:23])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH3:5].[OH-].[Na+]>C1COCC1.CO>[CH3:23][C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)([CH3:5])[C:3]([OH:24])=[O:2]
Reactant: COC(=O)C(C)(C)Oc1ccccc1Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Oc1ccccc1Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.8 %

Procedure:
To a solution of 433A (5.05 g, 15.2 mmol) in a mixed solvent of THF/MeOH (45 ml, 2/1) was added 2N NaOH (15.2 ml, 30.4 mmol). The mixture was stirred at rt for 2.5 h, concentrated. The residue was purified by flash chromatography on silica gel (2%-5% MeOH—CH2Cl2) gave 433B (4.38 g, 91%) as a light yellow solid.
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:24][O:25]CC1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]1=[O:18])C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:24][OH:25])[O:11][C@H:12]2[N:16]1[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: O=c1ccn([C@@H]2O[C@@]3(COCc4ccccc4)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=c1ccn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]1
Reaction time: 4 h

Procedure:
To a solution of compound 43 (0.35 g, 0.8 mmol) in absolute ethanol (2 m3) was added 20% palladium hydroxide over carbon (0.37 g) and the mixture was degassed several times with hydrogen and stirred under the atmosphere of hydrogen for 4 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloramethane/methanol (9:1, v/v) as eluent to give nucleoside 44 as a white solid material (0.16 g, 78%). δH (CD3OD) 7.88 (1H, d, J 8.1, 6-H), 5.69 (1H, d, J 8.1, 5-H), 5.55 (1H, s, 1′-H), 4.28 (1H, s, 2′-H), 4.04 (1H, s, 3′-H), 3.96 (1H, d, J 7.9, 1″-Ha), 3.91 (2H, s, 5′-H), 3.76 (1H, d, J 7.9, 1″-Hb). δC (CD3OD) 172.95 (C-4), 151.82 (C-2), 141.17 (C-6), 101.97 (C-5), 90.52, 88.50 (C-1′, C-4′), 80.88, 72.51, 70.50, 57.77 (C-2′, C-3′, C-5′, C-1″). FAB-MS m/z 257 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:27](I)[CH3:28]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([O:13][CH2:27][CH3:28])=[O:12])=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reaction time: 71 h
Yield: 95.1 %

Procedure:
To a suspension of (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (9.98 g, 27.9 mmol) and NaHCO3 (4.68 g, 55.7 mmol) in DMF (45 mL) is added Ethyl iodide (6.75 mL, 84 mmol) at room temperature under nitrogen. After stirring for 71 hours, the reaction is quenched with H2O (300 mL), and then precipitated solid is collected and washed with H2O (500 mL) to give (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (10.25 g, 94%). HPLC retention time=1.48 minutes (condition B); MS (ES+)=329.9 (m-tBu+2); 286.0 (m-Boc+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J=7.2 Hz, 3 H) 1.40 (s, 9 H), 2.43 (A of ABX, Jab=15.8 Hz, Jax=5.7 Hz, 1 H) 2.50 (B of ABX, Jab=15.8 Hz, Jbx=5.4 Hz, 1 H) 2.74-2.90 (m, 2 H) 4.11 (br s) 4.15 (q, J=7.1 Hz, 2 H) 5.04 (br d) 7.07 (d, J=8.3 Hz, 2 H) 7.40-7.43 (m, 2 H).
Reaction SMILES: [NH:1]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C@H:2]([C:12]([O:14]C(C)(C)C)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)[C@H](COCc1ccccc1)NN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1COCCN1
Product: N[C@@H](COCc1ccccc1)C(=O)O

Procedure:
Morpholino-Ser(OBn) was prepared from N-Fmoc-Ser(OBn). Esterification of N-Fmoc-Ser(OBn) with isobutylene in the presence of a catalytic amount of H2SO4 afforded N-Fmoc-Ser(OBn)-OtBu. The Fmoc group was removed with piperidine in CH2Cl2 to produce Ser(OBn)-OtBu. Reaction of Ser(OBn)-OtBu with 4-morpholinecarbonyl chloride in pyridine yielded morpholino-Ser(OBn)-OtBu. Morpholino-Ser(OBn)-OtBu was hydrolyzed with TFA in CH2Cl2 to yield morpholine-Ser(OBn).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16](OC)=[O:17])[CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:4].Cl.[NH2:26][C:27]([NH2:29])=[NH:28].C[O-].[Na+]>CN(C)C=O>[F:1][C:2]([F:24])([F:23])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([N:26]=[C:27]([NH2:29])[NH2:28])=[O:17])[CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:4]
Reactant: N=C(N)N
Reactant: COC(=O)c1cccc(-c2cccc(NS(=O)(=O)C(F)(F)F)c2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(N)=NC(=O)c1cccc(-c2cccc(NS(=O)(=O)C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.3 %

Procedure:
Methyl 3-(3-trifluoromethylsulfonylaminophenyl)-benzoate (1.7 g) was added to the mixture of guanidine hydrochloride (2.26 g) and 28% methanolic sodium methoxide (4.1 ml) in N,N-dimethylformamide (17 ml) and the reaction mixture was stirred for 6 hours at ambient temperature. After evaporating the solvent, the residue was poured into the mixture of ethyl acetate (50 ml) and water (50 ml). The mixture was adjusted to pH 6.2 with 10% hydrochloric acid. The crystalline product was collected by filtration, washed successively with water and methanol and dried in vacuo to afford 2-[3-(3-trifluoromethylsulfonylaminophenyl) benzoyl]guanidine (0.28 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:29])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[Cl:28])[C:17](=[O:19])[CH3:18])(C)(C)C>>[Cl:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8])=[O:29]
Reactant: Nc1cc(O)ccc1F
Reactant: CC(=O)C(Cc1ccc(F)cc1Cl)C(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(F)cc1Cl)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(2-chloro-4-fluorobenzyl)-3-oxothiobutyric acid S-tert-butyl ester.