Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].O.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[NH:19][N:18]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[Cl:33][C:29]1[CH:28]=[C:27]([NH:26][C:24]2[N:23]=[CH:22][N:21]=[C:20]3[NH:19][N:18]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:3]([N:2]([CH3:6])[CH3:1])=[O:4])=[CH:11][CH:12]=4)[C:25]=23)[CH:32]=[CH:31][CH:30]=1
Reactant: CN(C)C(=O)Cl
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1

Procedure:
A solution of 0.0503 ml (0.548 mmol) of dimethylcarbamoyl chloride in 0.5 ml of THF is added dropwise, with stirring, to a suspension, cooled to 0° C., of 150 mg (0.391 mmol) of 3-(4-aminomethyl-phenylamino)4-(3-chloro-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine hydrate (see Step 77.5) in 2.5 ml of THF and 0.079 ml (0.567 mmol) of triethylamine. The reaction mixture is stirred at RT for 17 hours and then filtered, and the filter residue is washed in succession with THF, water, THF and diethyl ether. 4-(3-Chloro-phenylamino)-3-[4-(dimethylamino-carbonylamino-methyl)-phenylamino]-1H-pyrazolo[3,4-d]pyrimidine having a water content of 1.22% is obtained; m.p. 238-240° C.; ESI-MS: (M+H)+=437.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[C:11]([OH:13])[C:10](=[O:14])[CH:9]=[C:8]2[CH3:15])[CH:2]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[C:11]([O:13][CH2:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[C:10](=[O:14])[CH:9]=[C:8]2[CH3:15])[CH:2]=1
Reactant: Cc1cc(=O)c(O)cn1-c1cccc(-c2ccccc2)c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(-c3cccc(-c4ccccc4)c3)c(C)cc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4.8 g (17.4 mmol) 1-biphenyl-3-yl-5-hydroxy-2-methylpyridin-4(1H)-one in 150 ml of DMF was added 4.1 g (26.1 mmol) PMBCl, and 12.0 g (87.0 mmol) K2CO3. The reaction was stirred at rt for 2 h, after which time water was added and a precipitate formed. The solid was collected by filtration and purified by flash chromatography (100 g silica gel, 0-20% MeOH:EtOAc) to afford 1-biphenyl-3-yl-5-[(4-methoxybenzyl)oxy]-2-methylpyridin-4(1H)-one. 1H NMR δ (ppm) (DMSO-d6): 7.84 (1 H, d, J=7.86 Hz), 7.77 (2 H, d, J=7.71 Hz), 7.73 (1 H, s), 7.64 (1 H, t, J=7.84 Hz), 7.53-7.47 (3 H, m), 7.46-7.39 (2 H, m), 7.38-7.30 (3 H, m), 6.93 (2 H, d, J=8.32 Hz), 6.23 (1 H, s), 4.89 (2 H, s), 3.77-3.70 (3 H, m), 2.03 (3 H, s). LCMS (M+H)+=398.3.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[N-:10]([C:13]#[N:14])[C:11]#[N:12].[Na+]>>[C:11]([N:10]=[C:13]([NH2:14])[NH:4][C:3]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=1[F:1])#[N:12]
Reactant: N#C[N-]C#N
Reactant: Nc1cc(F)ccc1F
Agent: [Na+]
Product: N#CN=C(N)Nc1cc(F)ccc1F

Procedure:
2,5-Difluoroaniline and sodium dicyanamide were procesed as described in Example 71A to provide the desired compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:26][C:25]4[C:24](=[O:27])[N:23]([CH2:28][CH2:29][CH3:30])[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH3:34])[C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:7][N:6]1[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[O:31]=[C:22]1[N:21]([CH2:32][CH2:33][CH3:34])[C:20]2[N:19]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH:8]4[CH2:7][N:6]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:45])[F:43])[CH:37]=5)[CH:5]([C:3]([OH:4])=[O:2])[CH2:9]4)=[CH:17][CH:16]=3)[NH:26][C:25]=2[C:24](=[O:27])[N:23]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(OCC4CC(C(=O)OC)N(Cc5cccc(C(F)(F)F)c5)C4)cc3)nc2n(CCC)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(OCC4CC(C(=O)O)N(Cc5cccc(C(F)(F)F)c5)C4)cc3)nc2n(CCC)c1=O
Reaction time: 2 h

Procedure:
A mixture of solution of 4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-phenoxymethyl]-1-(3-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid methyl ester (25 mg, 0.039 mmol) in THF (3 ml) and MeOH (1 ml) was added aq. solution of LiOH (3 mg, 0.079 mmol) in H2O (1 ml) at 0° C. and it was stirred for 2 hrs. Reaction mixture was concentrated, residue was diluted with water and acidified with aq. HCl. The aqueous layer was extracted with ethyl acetate and washed with brine. The ethyl acetate layer was concentrated and purified by column chromatography to offer 4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-phenoxymethyl]-1-(3-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid as viscous oil (18 mg, 75%).
Reaction SMILES: [CH2:1]([Br:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[Br-:12].[CH2:1]([P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCCCBr
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 64.7 %

Procedure:
A mixture of 14.1 g (60 mmol) of undecyl bromide and 15.7 g (60 mmol) of triphenylphosphine was refluxed in xylene for 15 hours, and the xylene was evaporated off. The mixture was added with ether and the supernatant was removed by decantation. This procedure was repeated thrice to obtain 19.3 g of undecyltriphenylphosphonium bromide. The bromide was dissolved in 200 ml of tetrahydrofuran and 20 ml (32 mmol) of a hexane solution (1.6 molar concentration) of 15% n-butyl lithium was added dropwise thereto under stirring and cooling with ice. After 10-minute stirring, a solution of 2.17 g (13 mmol) of (2-methoxycarbonylpyrrole)-4-acetaldehyde obtained in Synthesis Example 12 in 6 ml of tetrahydrofuran was added dropwise to the mixture under cooling with ice, and the mixture was allowed to react for 30 minutes. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was collected, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The residue obtained by evaporation was purified by a silica-gel column chromatography (eluent:ethyl acetate/hexane=1/10) to obtain 3.41 g of oil methyl 4-(2-tridecenyl)pyrrole-2-carboxylate. The yield was 86%.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][Cl:24]>CO>[Br-:19].[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][N+:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:1]
Reactant: ClCCCCBr
Reactant: CCCCCCCCN(C)CCCCCCCC
Solvent: CO
Product: CCCCCCCC[N+](C)(CCCCCl)CCCCCCCC
Product: [Br-]
Temperature: 68 °C
Yield: 98.9 %

Procedure:
To a 500 mL, round-bottomed flask equipped with air condensers and magnetic stirring was charged N-methyldioctylamine (201.83 grams, 0.790 moles), 1-bromo-4-chlorobutane (135.517 grams, 0.790 moles) and methanol (250 mL). The reaction was maintained at 68° C. for 48 hours. The reaction was cooled to room temperature. Solvent was removed by rotary evaporation until a thick oil remained. Solvent removal was continued under high vacuum at 50° C., yielding 333.53 grams of a thick brown oil.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([CH3:11])/[C:6](=[CH:12]\[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)/[C:5]1=[O:21])(=O)C.[H-].[Na+].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[CH:24](=[C:9]1/[C:8](=[O:10])[N:7]([CH3:11])/[C:6](=[CH:12]\[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)/[C:5](=[O:21])[NH:4]/1)\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(/C=C2/C(=O)N(C(C)=O)CC(=O)N2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(/C=c2/c(=O)[nH]/c(=C\c3ccccc3)c(=O)n2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.8 %

Procedure:
A mixture of (3Z)-1-Acetyl-3-(4-methoxybenzylidene)-4-methyl-2,5-piperazinedione (10) (200 mg, 0.69 mmol) and sodium hydride (60% dispersion in oil, 28 mg, 0.69 mmol) in dry DMF (10 ml) was stirred at room temperature for 18 h. Benzaldehyde (71 μl, 0.69 mmol) was then added and the reaction mixture stirred at room temperature for 18 h. It was then diluted with ethyl acetate (100 ml) and washed with brine (4×50 ml) . The organic phase was separated, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, dichloromethane containing 1% MeOH) to give 48 mg (21%) of a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[CH2:10](O)[CH2:11][CH2:12]CCCCC>S(=O)(=O)(O)O.O.C1(C)C=CC=CC=1>[C:7]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:5][CH2:6][CH2:10][CH2:11][CH3:12].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CCCCCCCCO
Agent: CC[C@H](C)[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)O
Temperature: 25 °C

Procedure:
13.1 g of isoleucine was dissolved in a solution of 10 g of concentrated sulfuric acid, 20 mL water, 20 mL of octanol, and 200 mL of toluene in a 500 mL round bottom flask equipped with a condenser and a Dean-Stark apparatus placed in an oil bath. The resulting solution was heated at reflux temperature until no more water could be distilled. The resulting solution was then cooled to room temperature, diluted with 120 mL of ethyl acetate and the organic layer washed with saturated aqueous sodium bicarbonate to neutralize acidic impurities, washed with saturated Brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting liquid distilled to provide isoleucine octanoate as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C:15]4[CH:20]=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:18]=[CH:17][N:16]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[CH:27]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH2:1]([C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C:15]4[CH:20]=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:18]=[CH:17][N:16]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1)[CH3:27]
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1ccc2c(n1)oc1c(-c3cc(-c4ccccc4)ccn3)cccc12
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1ccc2c(n1)oc1c(-c3cc(-c4ccccc4)ccn3)cccc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
2-methyl-8-(4-phenylpyridin-2-yl)benzofuro[2,3-b]pyridine (5.3 g, 15.76 mmol) was dissolved in 130 mL of THF. This solution was cooled in a dry ice bath to −78° C. Lithium diisopropylamide in THF (9.85 mL, 19.69 mmol) was added dropwise to the reaction mixture over a 10 minute period maintaining the temperature below −73° C. The reaction mixture was stirred at −78° C. for 2 hours. Iodomethane (3.35 g, 23.63 mmol) was dissolved in 20 mL of THF then was added dropwise via syringe to the cold reaction mixture. Stirring was continued as the reaction mixture gradually warmed to room temperature overnight. The reaction mixture was quenched with aqueous ammonium chloride then was extracted 2×300 mL ethyl acetate. The organics were combined, were washed with aqueous LiCl then were dried over magnesium sulfate. These organics were then filtered and concentrated under vacuum. The crude residue was dissolved in DCM and was loaded onto a silica gel column. The column was eluted with 5-8% ethyl acetate/DCM. The main set of product fractions were combined and concentrated under vacuum yielding 2-ethyl-8-(4-phenylpyridin-2-yl)benzofuro[2,3-b]pyridine (5.15 g, 14.70 mmol, 93% yield)
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][CH:5]1[C:10]2=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH:13][N:9]2[N:8]=[CH:7][NH:6]1.[Cl-].[NH4+]>[Zn].CO.O1CCCC1>[F:1][C:2]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:3]=1[O:4][CH:5]1[C:10]2=[C:11]([CH:14]([CH3:15])[CH3:16])[CH:12]=[CH:13][N:9]2[N:8]=[CH:7][NH:6]1
Reactant: CC(C)c1ccn2c1C(Oc1ccc([N+](=O)[O-])cc1F)NC=N2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccn2c1C(Oc1ccc(N)cc1F)NC=N2
Reaction time: 4 h
Yield: 10 %

Procedure:
To a heterogeneous mixture of 4-(2-fluoro-4-nitrophenoxy)-5-isopropyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine (0.044 g, 1.39 mmol, 10 equiv) in 1/1 anhydrous methanol/tetrahydrofuran (2 mL), at ambient temperature under nitrogen atmosphere, was added zinc dust (0.090 g, 0.139 mmol, 1.0 equiv) and ammonium chloride (0.075 g, 1.39 mmol, 10 equiv). The mixture was stirred for 4 h before the catalyst was filtered off and the filtrate was concentrated in vacuo to yield the title compound (0.040 g, 100%) as a solid, that was used without further purification. HRMS(ESI), 287.1308 (M+H)+ calc, 287.1300 (M+H)+ found.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:25].Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@H:30]([OH:43])[CH2:29]1.C(OC([NH:51][C:52]([CH3:66])([CH3:65])[CH2:53][CH:54]([C:58]1[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=1)[C:55](O)=[O:56])=O)(C)(C)C.Cl>C(Cl)Cl>[NH2:51][C:52]([CH3:66])([CH3:65])[CH2:53][CH:54]([C:58]1[CH:59]=[CH:60][C:61]([Cl:64])=[CH:62][CH:63]=1)[C:55]([N:40]1[CH2:39][CH2:38][N:37]([C:35]2[C:36]3[C@H:28]([CH3:27])[CH2:29][C@@H:30]([OH:43])[C:31]=3[N:32]=[CH:33][N:34]=2)[CH2:42][CH2:41]1)=[O:56].[ClH:25]
Reactant: CC(C)(CC(C(=O)O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)C(CC(C)(C)N)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HBTU (37 mg, 0.098 mmol) was added to a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (30 mg, 0.098 mmol) and 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-4-methylpentanoic acid (33 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (50 mL) and washed with brine (5×50 mL). The organic phase was dried and concentrated to afford the product. The product was treated with HCl to afford 4-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-methylpentan-1-one as HCl salt (22 mg, 49%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][OH:8])[CH2:2]1.[CH:9]1([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>O1CCCC1.C(O)(=O)C>[CH:9]1([CH2:15][N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][OH:8])[CH2:2]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=CC1CCCCC1
Reactant: OC[C@H]1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC[C@H]1CCCN(CC2CCCCC2)C1
Reaction time: 21 h
Yield: 59.9 %

Procedure:
To a solution of 900 mg of (3S)-3-piperidylmethanol in 60 ml of tetrahydrofuran, 1.05 g of cyclohexanecarbaldehyde, 0.54 ml of acetic acid and 2.5 g of sodium triacetoxyborohydride were successively added at room temperature by the order stated, followed by 21 hours' stirring at the same temperature. The reaction liquid was rendered acidic with 1N hydrochloric acid and washed with chloroform. The aqueous layer was rendered basic with 4N aqueous sodium hydroxide solution, followed by extraction with chloroform and drying over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 990 mg of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2[N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
To a suspension of 4′-fluoro-p-toluenesulfonanilide (486.6 g (1.80 mol) in acetic acid (955 ml), 97% fuming nitric acid (128.6 g (1.98 mol) was added dropwise, keeping the inner temperature at 45° C., over a period of 40 minutes. After completion of the addition, the reaction mixture was stirred at 50° C. for 2 hours and left to cool to room temperature. Water (2000 ml) was then added and the mixture was stirred for 30 minutes. The crystals separated were filtered and washed with water to give 543.5 g (97%) of 4′-fluoro-2′-nitro-p-toluenesulfonanilide as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].C(O)(=O)C>C(O)C>[NH2:23][C:21]1[CH:20]=[CH:19][C:3]([CH2:4][N:5]2[C:9]3=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]3[N:7]=[C:6]2[CH3:18])=[C:2]([Cl:1])[CH:22]=1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc([N+](=O)[O-])cc3Cl)c2n1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Yield: 94.1 %

Procedure:
Methyl 3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (705 mg) was suspended in ethanol (6 ml), and reduced iron (437 mg) and acetic acid (1.01 ml) were added. The mixture was refluxed under heating for 2 hr. Then, reduced iron (218 mg) and acetic acid (1.01 ml) were further added, and the mixture was refluxed under heating for 1 hr. The reaction mixture was filtered through Celite, the insoluble matter was washed with ethanol and the filtrate was concentrated under reduced pressure. To the concentrate were added a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate to make the aqueous layer alkaline. At this stage, part of the objective compound was precipitated. The precipitate was collected by filtration and the filtrate was partitioned. The organic layer was washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The objective compound that precipitated during neutralization was dissolved in a mixed solvent of methanol/chloroform (1/4), and the mixture was filtrated. Both filtrates were combined and concentrated under reduced pressure to give the objective compound (608 mg) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(N[N:16]1[CH:24]=[C:22](C)[C:20](=O)[NH:19][C:17]1=[O:18])=O.[N:25]1C=CC=CC=1>>[CH2:1]([O:8][C:9]([NH:25][C:20]1[CH:22]=[CH:24][NH:16][C:17](=[O:18])[N:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn(NC(=O)Cl)c(=O)[nH]c1=O
Reactant: c1ccncc1
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(Nc1cc[nH]c(=O)n1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Over a period of about 1 h, benzyloxycarbonyl chloride (52 ml; 0.36 mol) was added dropwise to a suspension of cytosine (8, 20.0 g; 0.18 mol) in dry pyridine (1000 ml) at 0° C. under nitrogen in oven-dried equipment. The solution then was stirred overnight, after which the pyridine suspension was evaporated to dryness, in vacuo. Water (200 ml) and 4N hydrochloric acid were added to reach pH~1. The resulting white precipitate was filtered off, washed with water and partially dried by air suction. The still-wet precipitate was boiled with absolute ethanol (500 ml) for 10 min, cooled to 0° C., filtered, washed thoroughly with ether, and dried, in vacuo. Yield 24.7 g (54%). M.p.>250° C. Anal. for C12H11N3O3. Found (calc.); C: 58.59(58.77); H: 4.55(4.52); N: 17.17(17.13). No NMR spectra were recorded since it was not possible to get the product dissolved.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7](O)=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH2:26]([O:33][C:34](=[O:46])[C@H:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:36][C:37](=[O:41])[C@H:38]([CH3:40])[NH2:39])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([O:33][C:34](=[O:46])[C@H:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:36][C:37](=[O:41])[C@H:38]([CH3:40])[NH:39][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)N[C@@H](C)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)N)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of acetylalanine (0.03 mole) and N-methylmorpholine (0.03 mole) in dry tetrahydrofuran (200 ml) at -20° to -25° is added isobutyl chloroformate (0.03 mole). After 10 minutes, a suspension of the crude alanylleucine benzyl ester hydrochloride (0.03+ mole) and N-methylmorpholine (0.04 mole) in tetrahydrofuran (25 ml) is added in portions over 1/2 hour. The mixture is allowed to warm to room temperature over a period of 2 hours and stirred overnight. The reaction mixture is evaporated to dryness and the residue is purified by chromatography on silica gel (200 gm) and elution with 10% methanol in chloroform to give acetylalanylalanylleucine benzyl ester.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C([N:14]([CH2:17][CH3:18])CC)C.[C:19]1([C:28](Cl)=[O:29])[CH:24]=[CH:23][CH:22]=[C:21]([C:25](Cl)=[O:26])[CH:20]=1>C(Cl)Cl.Cl>[O:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH2:1][NH:11][C:28](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH:14][CH2:17][C:18]4[CH:2]=[CH:3][C:4]5[O:5][CH2:6][O:7][C:8]=5[CH:9]=4)=[O:26])[CH:20]=3)=[CH:3][C:4]=2[O:5][CH2:6]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1ccc2c(c1)OCO2)c1cccc(C(=O)NCc2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.2 %

Procedure:
In methylene chloride (200 mL) was dissolved the piperonyl amine (12.8 g, 85 mmol) and triethyl amine (9.09 g, 90 mmol). To this was added in parts 1,3-benzenedicarbonyl dichloride (8.12 g, 40 mmol). The mixture was stirred at room temperature for 24 hours and then diluted with 1N hydrochloric acid (300 mL). The mixture was filtered to collect a solid. The solid was washed with 1N sodium hydroxide (50 mL) and then water (6×100 mL). The solid was dried at 65° C. for 3 hours at reduced pressure to give 15.08 g (87%) of a white solid. MS: M+1=433.3.