Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:15][CH2:16][CH3:17])=[C:4]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:18][O:1][C:2]1[C:3]([CH2:15][CH2:16][CH3:17])=[C:4]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: CCCc1c(C=O)cc([N+](=O)[O-])c(OC)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCc1c(C=O)cc([N+](=O)[O-])c(OC)c1OC
Yield: 64.4 %

Procedure:
A solution of the product from step (c) (40.2 g), potassium carbonate (46.5 g) and methyl iodide (20.9 ml) in dry dimethylformamide (150 ml) was stirred at 20° C. for 16 hours. The solvent was evaporated and the residue quenched with water. The aqueous phase was extracted with ethyl acetate which was washed with brine, dried, filtered and evaporated to leave a yellow oil (27.4 g), MS; m/e 283.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(=O)NCCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(C(=O)NCCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(2-phenylethylamino-carbonyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: CN1CCOCC1.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11](Cl)[CH:10]=1.[Cl:19]N1N=C(OC)C=C(OC)N1>C(OCC)(=O)C>[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[Cl:19]
Reactant: COC1=CC(OC)=NN(Cl)N1
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)O)cc1Cl

Procedure:
Separately, 23.5 g of N-Methylmorpholine is added to a mixture of 33.1 g of 4-Amino-chloro-benzoic acid 34.4 g of 2-Chloro-4,6-dimethoxytriazine (DMT-Cl) in 300 ml of ethyl acetate over 20-30 minutes at ambient temperature for 2-3 hours at 23-27° C. to obtain the DMT active ester of 4-Amino-3-chlorobenzoic acid. The mixture is cooled to 0° to +5° C. and 300 ml of purified water are added to the solution keeping temperature in the same range. The solution of the deprotected t-leucine product as the citrate salt is added at 0° C. to +5° C. over 30-60 minutes, the reaction mixture is then brought to pH 6.5-7.5 by adding 30% sodium hydroxide (approx. amount: 71 ml), and stirred 6-7 hrs at 20° to 25° C. After completion of the reaction, the phases are separated and the organic layer added to sodium bisulfate solution (15 g of sodium bisulfate in 235 ml of water) and stirred for 3 hrs at 20° C. to 25° C. The phases are separated and the organic layer is washed four times with water (150 ml each), twice with sodium bicarbonate solution (total: 20 g of sodium bicarbonate in 400 ml of water), and once with 150 ml of water. To the solution is added 10 g of activated charcoal and 10 g of Dicalite and filtered and the solids washed with 100 ml of ethyl acetate. The filtrate was distilled under vacuum to a volume of 200 ml at <40° C. when the resultant mixture crystallizes. Ethyl acetate (150 ml) was added to a total volume of 350 ml. N-heptane (300 ml) was added over 2 hrs and after stirring the slurry for 3 hrs at 200 to 250, the solid was filtered, washed with ethyl acetate/N-Heptane (100 ml, 1:1) and dried at 60° C. under vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3.O.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CO>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCBr
Reactant: O=c1c2ccc(O)cc2oc2cc(O)ccc12
Solvent: CO
Solvent: O
Product: CCCCCCCCOc1ccc2c(=O)c3ccc(O)cc3oc2c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 30 %

Procedure:
3,6-Dihydroxy xanthone (1,20 mmol) was dissolved in hot mixture of basic water (80 mmol of Na2CO3 in 100 ml of water) and 50 ml of methanol. After the compound was completely dissolved, a methanol solution of octyl bromide (40 mmol in 50 ml of methanol) was added dropwise and the reaction mixture was stirred rigorously for 120 hours at refluxing temperature. The reaction mixture was cooled to room temperature giving a precipitate. This white precipitate was then filtered, washed with water, and washed with hot hexane to remove the disubstituted side product. 3-Octoxy-6-hydroxy xanthone was obtained in 30% yield. 1HNMR (DMSO): d11.0(1H,s), 8.05 (1H,d,J=6.0 Hz), 8.02 (1H,d,J=5.8 Hz), 7.08 (1H,s), 7.00 (1H,d,J=8.8 Hz), 6.89 (1H,d,J=8.8 Hz), 6.85 (1H,s), 4.43 (2H,t,J=6.2 Hz), 1.8(2H,M), 1.3 (10H,m), 0.9 (3H,t).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[C:6]([Br:8])[CH:7]=1.BrBr.N>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]2[S:11][C:10]([NH2:12])=[N:9][C:4]=2[CH:3]=1
Reactant: NC(=S)Nc1cc(Br)cc(Br)c1
Agent: BrBr
Agent: N
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc2cc(Br)cc(Br)c2s1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
To a solution of (3,5-dibromo-phenyl)-thiourea (35 g, 0.11 mol) in CHCl3 (600 mL) at −55-60° C. was added dropwise a solution of Br2 (40.40 g, 0.25 mol, in 100 ml of CHCl3) over a period of 1 h. The reaction mixture was stirred at −55-60° C. for 15 min followed by refluxing at 70-75° C. for 3 h. The reaction mixture was cooled to room temperature and filtered to get the crude residue that was washed with hexane and diethyl ether. The solid thus obtained was dissolved in H2O, basified with aqueous ammonia solution to pH 10-12 and stirred for 30 min. The solid thus obtained was filtered and washed with water to get the desired product (34.0 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:38]2[CH:42]=[N:41][N:40]=[N:39]2)=[C:6]([C:8]#[C:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:13]2[C:22]([NH:24][C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[O:11])[CH:7]=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.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:38]2[CH:42]=[N:41][N:40]=[N:39]2)=[C:6]([C:8]#[C:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:13]2[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=2)=[O:23])=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2c3ccccc3CCN2C(=O)C#Cc2cc(Cl)ccc2-n2cnnn2)cc1
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: O=C(O)c1ccc(NC(=O)[C@@H]2c3ccccc3CCN2C(=O)C#Cc2cc(Cl)ccc2-n2cnnn2)cc1
Reaction time: 24 h

Procedure:
(S)-tert-Butyl 4-(2-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)propioloyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoate: Combined 48C (0.055 g, 0.221 mmol), 3B (0.078 g, 0.221 mmol), BOP (0.098 g, 0.221 mmol), and DIEA (0.039 mL, 0.221 mmol) in DMF (1 mL). After 24 h, the reaction was partitioned with H2O (10 mL) and brine (10 mL) and EtOAc (60 mL). The organic layer was washed with brine (10 mL) and dried (MgSO4). MS (ESI) m/z: 582.9 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([NH:6][C:7]([C@@H:9]([NH2:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[C:3]([OH:5])=O.[NH2:18][C@H:19]([C:21]([NH:23][C@H:24]([C:26]([OH:28])=[O:27])[CH3:25])=[O:22])[CH3:20].[OH-].[Na+]>>[NH2:17][C@H:9]([C:7]([NH:6][C@H:2]([C:3]([NH:18][C@H:19]([C:21]([NH:23][C@H:24]([C:26]([OH:28])=[O:27])[CH3:25])=[O:22])[CH3:20])=[O:5])[CH3:1])=[O:8])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O

Procedure:
0.2 ml of aqueous solution containing 2 mM Mal-Phe-Ala OEtCl, 50 mM H-Ala-Ala-OH, 25 mM NaOH and 0.15 mg/ml papain are deep-frozen. Subsequently the reaction mixture is kept at -25° C. until the Mal-Phe-Ala-OEtCl is consumed. Following thawing, the yield is determined analytically by RP-HPLC and amounts to 79% of theory.
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][CH2:9][C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:53]=[N+:54]=[N-:55])(C2C=CC=CC=2)=O)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[N:53]([C@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][CH2:9][C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH2:4][CH2:3]1)=[N+:54]=[N-:55]
Reactant: C[C@@H](CO[C@H]1CC[C@@H](O)CC1)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](CO[C@H]1CC[C@H](N=[N+]=[N-])CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl {(1S)-2-[(cis-4-hydroxycyclohexyl)oxy]-1-methylethyl}carbamate (5.00 g), triphenylphosphine (7.20 g) and diphenylphosphorylazide (5.03 g) in toluene (200 mL) was added dropwise a solution (1.9 M, 14.4 mL) of diisopropyl azodicarboxylate in toluene, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in diethyl ether, and the precipitate was removed by filtration. The filtrate was concentrated, and the residue was purified by silica gel chromatography(hexane/ethyl acetate) to give the title compound (1.05 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([NH2:24])[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1>CN(C)C=O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:3]2[C:2]([NH:23][CH:20]3[CH2:21][CH2:22][CH:17]([NH2:24])[CH2:18][CH2:19]3)=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1
Reactant: Clc1ncnc2scc(-c3ccccn3)c12
Reactant: NC1CCC(N)CC1
Solvent: CN(C)C=O
Product: NC1CCC(Nc2ncnc3scc(-c4ccccn4)c23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 100-mL round-bottom flask was charged with 2-[4-chlorothieno[2,3-d]pyrimidin-5-yl]pyridine (1.0 g, 4.04 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), TEA (1.2 g, 11.86 mmol, 2.94 equiv) and cyclohexane-1,4-diamine (2.8 g, 24.52 mmol, 6.07 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 4×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 4×50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.9 g (69%) of 1-N-[5-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl]cyclohexane-1,4-diamine as yellow oil. MS: m/z 326 (M+H)+.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[CH3:9]>>[F:2][C:3]1[CH:4]=[C:5]([S:10]([NH2:1])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Reactant: N
Product: Cc1ccc(S(N)(=O)=O)cc1F

Procedure:
To ˜20 mL of liquid ammonia at −78° C. was added 2.1 g (10 mmol) of 3-fluoro-4-methyl benzenesulfonyl chloride. The excess ammonia was then naturally evaporated to dryness overnight at room temperature. The crude sulfonamide was partitioned methylene chloride (100 mL) and water (100 mL). The aqueous phase was further extracted with methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate. Evaporation of the solvents afforded 1.9 g of 3-fluoro-4-methylbenzenesulfonamide as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[CH3:26][CH:27]1[NH:31][C:30](=[O:32])[CH2:29][CH2:28]1>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:31]4[CH:27]([CH3:26])[CH2:28][CH2:29][C:30]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: CC1CCC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4C(=O)CCC4C)cc3F)CC2)c(C)c1
Yield: 39 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 111 and 5-methylpyrrolidin-2-one (48 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (81 mg) was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])C.N[C@H:11](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:4][CH3:6])[CH3:11]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
1.07 (1), Leu; 5.19 (5), Tyr; 0.98 (1),
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](OC2C=CC=CC=2)=[N:18][C:19]#[N:20])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[C:19]([NH:18][C:17](=[N:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[O:16][C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)#[N:20]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CNC(=Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 66.6 %

Procedure:
To a solution of 3,5-dichloroaniline (11 mmol, 1.79 g) in dichloromethane (25 ml), diphenylcyanocarbonimidate (10 mmol, 2.38 g) and triethylamine (11 mmol, 1.53 ml) were added. The reaction mixture was stirred under nitrogen for 65 h at room temperature. After concentration the residue was stirred with water, the water was decanted followed by concentration. The residue was stirred with toluene and the solid was collected by filtration giving 2.04 g of the title compound (67%); 1H-NMR (CDCl3): δ 7.12 (d, 2H), 7.22 (s, 1H), 7,35 (m, 3H), 7.45 (d, 2H), 9.4 ppm (br s,1H). EI SP/MS: 305 (M+), 307 (M+2), 309 (M+4).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9](B(O)O)=[C:8]([CH2:17][CH3:18])[CH:7]=2)=[CH:4][CH:3]=1.[C:21]([O-:24])(=[O:23])[CH3:22].[C:25]([O-:28])(=[O:27])[CH3:26].[C:29]([O-:32])(=[O:31])[CH3:30].C([O-])(=O)C.[Pb+4:37].CCCCCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:21]([O-:24])(=[O:23])[CH3:22].[C:25]([O-:28])(=[O:27])[CH3:26].[C:29]([O-:32])(=[O:31])[CH3:30].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([Pb+3:37])=[C:8]([CH2:17][CH3:18])[CH:7]=2)=[CH:4][CH:3]=1
Reactant: [Pb+4]
Reactant: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1B(O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1[Pb+3]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.5 %

Procedure:
4′-Chloro-3,5-diethylbiphen-4-ylboronic acid (2.1 g, 0.007 mol) is added to a mixture of lead tetraacetate (3.67 g, 0.008 mol) and mercuric acetate (0.12 g, 5 mol %) in chloroform (15 ml) and the reaction mixture is stirred for 15 minutes at room temperature under an atmosphere of nitrogen, then stirred and heated at 40° C. for 4 hours. The reaction mixture is cooled to ambient temperature, filtered through a plug of diatomaceous earth and concentrated under reduced pressure to give an orange solid. Trituration with hexane (20 ml) affords a yellow solid which is dried under high vacuum. The solid is dissolved in chloroform (50 ml) and anhydrous potassium carbonate (11.6 g, 0.084 mol) is added. The suspension is stirred rapidly for 10 minutes, then filtered through plug of diatomaceous earth. The filtrate is concentrated under reduced pressure to give 4′-chloro-3,5-diethylbiphen-4-yllead triacetate (2.0 g) as a cream solid.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH2:17]Br>C(Cl)(Cl)Cl>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH2:17][N:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCNCCNCCN1
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Solvent: ClC(Cl)Cl
Product: COc1ccc([N+](=O)[O-])cc1CN1CCNCCNCCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a stirred chloroform solution (20 ml) containing 2.9 g of 1,4,7,10-tetraazacyclododecane (16.8 mmole) was added a chloroform solution (20 ml) containing 2.1 g of 2-methoxy-5-nitrobenzyl bromide (8.5 mmole) in one portion. After stirring at room temperature for three hours the reaction mixture was filtered and the filtrate concentrated (in vacuo) to give a residue which was chromatographed (silica, Solvent System 3). The monoalkylated product was isolated in 79 percent yield (MP=154°-156° C.), and characterized by:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:5](=[NH:6])[NH:11][OH:12])[CH:7]=[CH:8][CH:9]=1
Reactant: NO
Reactant: N#Cc1cccc(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1cccc(N)c1
Temperature: 25 °C
Yield: 103.5 %

Procedure:
To a stirred solution of 3-aminobenzonitrile (4.0 g) (available from Aldrich) in ethanol (100 ml) was added hydroxylamine hydrochloride (4.7 g) and potassium carbonate (14.0 g) and the mixture heated under reflux for 22 h. After cooling to room temperature the mixture was filtered through ‘hyflo’ filter aid, the residue washed with ethanol, and the filtrates concentrated in vacuo to give the title compound as a viscous oil (5.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[NH4+].[Cl-].O>C(O)C.[Fe]>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])c(C2=CCCCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)C(C(=O)OC)c1ccc(N)c(C2=CCCCC2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of 2-(3-cyclohex-1-enyl-4-nitro-phenyl)-malonic acid dimethyl ester (as prepared in the previous step, 200 mg, 0.600 mmol), iron powder (168 mg, 3.00 mmol) and NH4Cl (321 mg, 6.00 mmol) in 6 mL of ethanol was stirred at 80° C. for 16 h. After cooling to RT, the mixture was treated with 30 mL of H2O and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (30% EtOAc-hexane) to give 129 mg (71%) of the title compound as a faint yellow oil: Mass spectrum (ESI, m/z): Calcd. for C17H21NO4, 304.2 (M+H). found 304.1.
Reaction SMILES: O[CH2:2][CH:3]1[CH:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][CH:6]2[CH:5]([N:13]2[CH:21]=[N:20][C:19]3[C:18](=[O:22])[NH:17][C:16]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[N:15][C:14]2=3)[O:4]1.[CH2:29]([O:31][P:32]([CH:37]=CC1C(OC(=O)C2C=CC=CC=2)C(OC)C(N2C=NC3C(=O)NC(NC(=O)C(C)C)=NC2=3)O1)([O:34][CH2:35][CH3:36])=[O:33])[CH3:30]>>[CH2:29]([O:31][P:32]([CH:37]=[CH:2][CH:3]1[CH:7]2[CH:6]([O:10][C:9]([CH3:11])([CH3:12])[O:8]2)[CH:5]([N:13]2[CH:21]=[N:20][C:19]3[C:18](=[O:22])[NH:17][C:16]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])=[N:15][C:14]2=3)[O:4]1)(=[O:33])[O:34][CH2:35][CH3:36])[CH3:30]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2C2OC(CO)C3OC(C)(C)OC32)c(=O)[nH]1
Reactant: CCOP(=O)(C=CC1OC(n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C(OC)C1OC(=O)c1ccccc1)OCC
Product: CCOP(=O)(C=CC1OC(n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C2OC(C)(C)OC12)OCC
Yield: 64 %

Procedure:
Compound 18.3 (1.7 g, 64% yield) was was synthesized from compound 18.2 (2.0 g, 5.09 mmol) using the procedure described for the preparation of compound 16.7.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH:16]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])([CH3:18])[CH3:17].O>CC(C)=O>[CH3:17][CH:16]([O:19][CH2:20][CH2:21][CH2:22][NH:23][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH3:18]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: CC(C)OCCCN
Solvent: O
Solvent: CC(C)=O
Product: CC(C)OCCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 66.4 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mole) and 3-isopropoxy-1-propylamine (3.51 g, 0.030 mole) was heated at 140° C. for 5 hrs. After standing at ambient temperature for 18 hrs the mixture was dissolved in acetone (20 ml) and the solution poured into water (120 ml). A solid formed rapidly and was collected by filtration and dried at ambient temperature. The solid (2.80 g, 89%) was recrystallized from toluene-isooctone to yield 2.08 g of a fluffy white solid, m.p. 106°-108° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)=[CH:4][N:3]=1>C(O)C.C(O)(=O)C.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][N:3]=1
Reactant: Nc1ncc(C2CCN(Cc3ccccc3)CC2)c(N)n1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ncc(C2CCNCC2)c(N)n1

Procedure:
A solution of 26 g of 2,4-diamino-5-(1-benzyl-4-piperidinyl)pyrimidine in 700 ml of ethanol and 20 ml of acetic acid was hydrogenated over 5 g of Pd/C 10% at room temperature and normal pressure up to the standstill of the hydrogen uptake, whereupon it was filtered off from catalyst. The filtrate was concentrated and the crystalline residue was dissolved in 100 ml of water. Chromatography on Dowex 1 (×10 200-400 mesh) (a cation exchange resin) gave 2,4-diamino-5-(4-piperidyl)-pyrimidine of melting point 230°-231° C. (dec.) (from water).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]([O:16][CH3:17])=[N:14][C:13]2[C:8]1=[N:9][C:10]([O:19][C@@H:20]([CH3:24])[CH2:21][CH2:22][CH3:23])=[N:11][C:12]=2[NH2:18].C(N(CC)CC)C.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C>[CH3:24][C@H:20]([O:19][C:10]1[N:9]=[C:8]2[C:13]([N:14]=[C:15]([O:16][CH3:17])[N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:12]([NH2:18])[N:11]=1)[CH2:21][CH2:22][CH3:23]
Reactant: C1CCNCC1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1
Temperature: 70 °C
Yield: 51.9 %

Procedure:
9-(5-Chloropentyl)-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine (80 mg, 0.225 mmol), triethylamine (0.031 ml, 0.225 mmol) and piperidine (0.045 ml, 0.45 mmol) were suspended in DMF (3 ml) and the mixture heated to 70° C. for 18 hours. The solvent was removed and the residue partitioned between DCM (4 ml) and saturated sodium bicarbonate (4 ml). The aqueous phase was re-extracted with further DCM and the combined organic extracts were concentrated and the residue dissolved in 1:1 MeOH:DMSO (1 ml) and purified by MDAP (Method A). The product-containing fractions were combined and evaporated under a stream of nitrogen to give the title compound (47.2 mg).