Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][N:15]([CH2:18][C:19]([OH:21])=O)[C:14](=[O:22])[N:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CC(C)N=C=NC(C)C.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][C:33]1=[O:38]>C1C=CC=CC=1>[C:1]([NH:11][C:12]1[CH:17]=[CH:16][N:15]([CH2:18][C:19]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][C:33]2=[O:38])=[O:21])[C:14](=[O:22])[N:13]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C1CNCCN1
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Agent: CC(C)N=C=NC(C)C
Solvent: c1ccccc1
Product: O=C(Nc1ccn(CC(=O)N2CCNCC2=O)c(=O)n1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
(N4-CBz-cytosin-1-yl)acetic acid (2.42 g, 8 mmol) was azeotroped with benzene (3×25 mL) and dried under vacuum. 32 mL of anhydrous DMF was added under N2 followed by the addition of DIC (1.57 mL, 8 mmol). The reaction was stirred at room temperature for 2-3 minutes, then treated with piperazinone (8.8 mmol, 881.1 mg), and the reaction mixture was left to stir for 48 hours. The reaction mixture was concentrated by rotary evaporation, washed successively with 0.1 N citric acid solution (2×10 mL) and water (2×15 mL), and then dried in a dessicator, affording N-[(N4-CBz-cytosin-1-yl)acetyl]-piperazinone as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]3[CH2:18][CH:19]([CH2:21][CH2:22][C:23]([N:25]4[CH2:30][CH2:29][N:28]([C:31]5[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=5)[CH2:27][CH2:26]4)=O)[O:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:10]=2[CH3:38])=[CH:5][CH:4]=1.Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]3[CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][N:25]4[CH2:26][CH2:27][N:28]([C:31]5[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=5)[CH2:29][CH2:30]4)[O:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:10]=2[CH3:38])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(C)c3cccc4c3n2CC(CCC(=O)N2CCN(c3cc(C)ccn3)CC2)O4)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(C)c3cccc4c3n2CC(CCCN2CCN(c3cc(C)ccn3)CC2)O4)cc1

Procedure:
1 g of 2,3-dihydro-5-(4-methoxyphenyl)-6-methyl-2-[3-(4-(4-methylpyridin-1-yl)piperazin-1-yl) -3-oxopropyl]pyrrolo[1,2,3-de]-1,4-benzoxazine (prepared according to Example 6)) was dissolved in 15 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. 12 ml of a 1 molar borane-tetrahydrofuran complex were added to the solution. The reaction mixture was stirred and heated to reflux for 2 hours. 25 ml of a 6N hydrochloric acid solution were then added and the reaction mixture was stirred for 24 hours. The precipitate formed was dissolved in water which was rendered alkaline (pH=12), and the solution was extracted with dichloromethane. The organic extracts were dried and evaporated. The crude product remaining was purified by column chromatography using dichloromethane containing 2% ethanol as an eluent. The purified title compound was poured into 3N isopropanolic hydrochloric acid solution for conversion into its dihydrochloride salt. 0.6 g of 2,3-dihydro-5-(4-methoxyphenyl)-6-methyl-2-[3-(4-(4-methylpyridin-2-yl)piperazin-1-yl)propyl]pyrrolo[1,2,3-de]-1,4-benzoxazine. 2HCl.0.7H2O was obtained as yellow crystals having a melting point of 248° to 249° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:3]1>[Pd]>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:3]1
Reactant: CC(=O)NCC1CC(=O)c2ccccc2O1
Agent: [Pd]
Product: CC(=O)NCC1CC(O)c2ccccc2O1

Procedure:
Starting from the compound N-(4-oxochroman-2-ylmethyl)acetamide 1, the carbonyl group is hydrogenated to the hydroxyl group with noble-metal catalysis, for example using Pd on carbon (50% water-moist), to give the compound N-(4-hydroxychroman-2-ylmethyl)acetamide 2. The acetyl group is cleaved off using a base, for example sodium hydroxide. Addition of an acid gives the acid-addition salt 3 of 2-aminomethylchroman-4-ol. A further noble metal-catalysed hydrogenation generates the acid-addition salt 4 of 2-aminomethylchromane.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C(O)CCC>[Cl:18][C:16]1[CH:17]=[C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]2)[CH:13]=[N:14][CH:15]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cncc(Cl)c2)CC1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2cncc(Cl)c2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(5-chloro-pyridin-3-yloxy)-cyclohexanecarboxylic acid methyl ester (0.19 g, 0.70 mmol) and hydrazine hydrate (0.14 ml, 2.8 mmol) in n-butanol (0.5 ml) was heated at 120° C. for 18 h. After cooling to room temperature the reaction mixture was triturated in toluene (100 ml). The product was collected by filtration and dried in vacuo to give the crude title compound (0.15 g, 79%) as white solid, which was used in the next step without further purification. MS m/e: 270 (M+H+)
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([O-:25])=[O:24])[CH2:21][CH2:20]1.C([N+](CCCC)(CCCC)CCCC)CCC.F[C:46]1[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.CS(C)=O.O>[N+:52]([C:49]1[CH:50]=[CH:51][C:46]([N:19]2[CH2:27][CH2:26][CH:22]([C:23]([OH:25])=[O:24])[CH2:21][CH2:20]2)=[CH:47][CH:48]=1)([O-:54])=[O:53]
Reactant: O=C([O-])C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: O=C(O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 75 °C
Yield: 87.4 %

Procedure:
To a suspension of isonipocotic acid (8.3 g, 64 mmol) in methanol (250 mL) is added tetrabutylammonium hydroxide (40% aqueous solution, 42 mL). Solvents were then removed under reduced pressure. Residual water is removed by azeotropic distillation with toluene. The semisolid tetrabutylammonium isonipecotate is dried under high vacuum. To a solution of tetrabutylammonium isonipecotate (64 mmol) in dimethylsulfoxide (150 mL) is added 4-fluoronitrobenzene (7.5 mL, 71 mmol) and potassium carbonate (9.6 g, 70 mmol). The reaction mixture is heated in a 75° C. oil bath for three hours and then allowed to cool to room temperature. Water is added, followed by concentrated hydrochloric acid to bring the mixture to pH 6. The precipitated material is collected by filtration, washed with acetonitrile, and dried under house vacuum to provide 1-(4-nitrophenyl)piperidine-4-carboxylic acid as a yellow powder (14 g, 88%).
Reaction SMILES: O[C:2]1([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH:3]1[CH3:7].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:31][N:27]1[CH2:28][CH2:29][CH2:30][N:24]([C:21]2[CH:22]=[CH:23][C:18]([N:13]3[C:14](=[O:17])[C:15]4[S:16][C:8]([C:2]5[CH2:6][CH2:5][O:4][C:3]=5[CH3:7])=[CH:9][C:10]=4[N:11]=[CH:12]3)=[CH:19][CH:20]=2)[CH2:25][CH2:26]1
Reactant: CC1OCCC1(O)c1cc2ncn(-c3ccc(N4CCCN(C)CC4)cc3)c(=O)c2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1=C(c2cc3ncn(-c4ccc(N5CCCN(C)CC5)cc4)c(=O)c3s2)CCO1

Procedure:
6-(3-Hydroxy-2-methyltetrahydrofuran-3-yl)-3-[4-(4-methyl[1,4]diazepan-1-yl)phenyl]-3H-thieno[3,2-d]pyrimidin-4-one and p-toluenesulfonic acid were reacted by method AA. The product with the molecular weight of 422.55 (C23H26N4O2S) was obtained in this way; MS (ESI): 423 (M+H+).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][C@@H:15]([OH:17])[CH2:14][N:13]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C)C=O.O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]([N:13]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:12]2[CH2:11][N:31]=[N+:32]=[N-:33])=[O:19])=[CH:23][CH:24]=1
Reactant: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2CN=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxypyrrolidine-2-methanol p-toluenesulfonate (8.7 g: 20 mmole) in dimethylformamide (60 ml), a solution of sodium azide (1.56 g) in water (6 ml) is added. The mixture is stirred at 80° C. overnight. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is successively washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo to give crude (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxy-2-azidomethylpyrrolidine (5.6 g). Yield: 92%. NMR δ(CDCl3) ppm: 1.95 to 2.1(m, 2H), 3.2 to 3.8(m, 3H), 3.81(s, 3H), 3.83 to 4.6(m, 3H), 5.07(s, 2H), 6.89(d, J=8.8 Hz, 2H), 7.31(d, J=8.8 Hz, 2H). IR ν (CHCl3) cm-1 : 3420, 2100, 1689.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][N:9]=[C:10]2O)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:12]=2)[CH:7]=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nncc2ccc(C(F)(F)F)cc12
Product: FC(F)(F)c1ccc2cnnc(Cl)c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Into a 50 mL round-bottom flask, was placed 7-(trifluoromethyl)phthalazin-1-ol (prepared as described in the previous step, 1.6 g, 7.48 mmol, 1.00 equiv) and POCl3 (12 mL). The reaction mixture was stirred for 2 h at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of dichloromethane, washed with 3×5 mL of H2O, dried (Na2SO4), and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with CH3CN/H2O (10:4). The title compound was obtained as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1.C(O)(=O)C>CN(C=O)C.O>[CH2:3]([O:10][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
Oil-free NaH (1.9 g,~5 eq.) was suspended in DMF (30 ml) and the suspension was cooled in an ice bath. Benzyl alcohol (8.6 ml, ~5.2 eq.) was added slowly to the suspension via syringe. The resulting reaction mixture was stirred at 0° C. for 20 min., after which it was transferred to a precooled (0° C.) solution of 6-chloronicotinic acid (2.5 g, 15.9 mmol) in DMF (30 ml). Additional DMF (20 ml) was added to the reaction mixture to facilitate stirring. The reaction mixture was refluxed for 2 hours. Aqueous acetic acid 5% (by volume) was added to the cooled reaction mixture, and the resultant acidic mixture was extracted (3x) with ethyl acetate. The organic layers were combined, washed with brine and the solvent was removed to give a yellow liquid, from which a white solid was obtained after addition of water. Recrystallization from acetone/water gave 6-benzyloxynicotinic acid (4, Scheme I, 88% yield) as colorless needles.
Reaction SMILES: O=S1(=O)CCN(CC[NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([CH:46]([CH3:48])[CH3:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)CC1.Cl[CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][CH:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]1>>[CH:46]([C@H:43]1[C@@H:12]2[C@@H:13]3[C@@:26]([CH3:29])([CH2:27][CH2:28][C@@:11]2([NH:10][CH2:51][CH2:52][N:53]2[CH2:58][CH2:57][CH:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]2)[CH2:45][CH2:44]1)[C@@:25]1([CH3:30])[C@@H:16]([C@:17]2([CH3:42])[C@@H:22]([CH2:23][CH2:24]1)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=1)[CH2:19][CH2:18]2)[CH2:15][CH2:14]3)([CH3:48])[CH3:47]
Reactant: CC(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(=O)(=O)C1CCN(CCCl)CC1
Product: CC(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described in above for the synthesis of 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 1-(2-chloroethyl)-4-(methylsulfonyl)piperidine (prepared as described below) as the alkylating reagent in Step 3. The product was isolated as a white solid (24 mg, 36%). LCMS: m/e 723.56 (M+H)+, 2.28 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.02 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 3.77-3.63 (m, 2H), 3.62-3.54 (m, 3H), 3.50 (d, J=5.5 Hz, 1H), 3.35 (td, J=11.4, 3.7 Hz, 1H), 3.08-2.89 (m, 2H), 3.02 (s, 3H), 2.50 (d, J=13.1 Hz, 1H), 2.42-2.29 (m, 2H), 2.28-1.03 (m, 28H), 1.21 (s, 3H), 1.12 (s, 3H), 1.08 (s, 3H), 1.01 (d, J=11.3 Hz, 1H), 0.93 (d, J=6.7 Hz, 4H), 0.86 (d, J=6.7 Hz, 4H), 0.83 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:8]2=[O:25])=[C:4]([F:28])[CH:3]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+].[C@@H]1(N)CCCC[C@H]1N>CS(C)=O>[F:28][C:4]1[CH:3]=[C:2]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:27]=[CH:26][C:5]=1[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:8]1=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(Br)cc3F)C2=O)CC1
Reactant: CS(=O)[O-]
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
(S)-tert-Butyl 4-(3-(4-bromo-2-fluorophenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.8 g, 3.9 mmol) was dissolved in DMSO (30 mL) and purged with nitrogen. Sodium methanesulfinate (0.60 g, 5.9 mmol) and trans-cyclohexane-1,2-diamine (0.19 mL, 1.6 mmol) were added followed by Cu(I) triflate benzene complex (0.20 g, 0.39 mmol). The reaction was plunged into a 110° C. oil bath under nitrogen and stirred overnight. The reaction was cooled to ambient temperature, partitioned between water and EtOAc, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (S)-tert-butyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.6 g, 3.5 mmol, 89% yield) as a white solid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([NH:23]C=O)=[N:17][C:18]=2Cl)C1C=CC=CC=1.C(O)=[O:27]>[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:27])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2
Reactant: O=CO
Reactant: O=CNc1nc(Cl)c2ncn(OCCCOCc3ccccc3)c2n1
Agent: [Pd]
Product: Nc1nc2c(ncn2OCCCO)c(=O)[nH]1
Yield: 33 %

Procedure:
9-(3-Benzyloxyprop-1-oxy)-6-chloro-2-formamidopurine (3.40 g, 9.41 mmol) in 80% formic acid (100 ml) was heated at 100° C. for 1 hour. The reaction mixture was then cooled and stirred with 10% palladium on charcoal (2.0 g) under an atmosphere of hydrogen at 20° C. for 45 minutes. After removal of the catalyst, the solution was evaporated and the residue was treated with water (50 ml) and concentrated aqueous ammonia (4 ml) at 100° C. for 15 minutes. The solution was then cooled and evaporated under reduced pressure. Recrystallisation of the residue from water afforded 9-(3-hydroxyprop-1-oxy)guanine (800 mg, 33%). 1H NMR: δH [(CD3)2SO] 1.80 (2H, quintet, J=6.3, 6.6 Hz, CH2CH2CH2), 3.55 (2H, quartet, J=5.50, 5.8 Hz, CH2OH), 4.32 (2H, t, J=6.6 Hz, CH2ON), 4.57 (1H, t, J=5.5 Hz, D2O exchangeable, OH), 6.57 (2H, br.s, D2O exchangeable, NH2), 7.91 (1H, s, H-8), 10.63 (1H, br.s, D2O exchangeable, H-1).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([OH:33])=O)=[O:27].[NH2:37][C@@H:38]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C@H:39]([OH:52])[CH2:40][NH:41][CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[C:47]([CH:49]([CH3:51])[CH3:50])[CH:48]=1.CCN(C(C)C)C(C)C.O1C2C=CC=CC=2C=C1CNC(=O)OC(C)(C)C>C(Cl)Cl>[OH:52][C@H:39]([CH2:40][NH:41][CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[C:47]([CH:49]([CH3:51])[CH3:50])[CH:48]=1)[C@@H:38]([NH:37][C:31]([C:30]1[CH:29]=[C:28]([CH:36]=[CH:35][CH:34]=1)[C:26]([O:25][CH3:24])=[O:27])=[O:33])[CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CC(C)c1cncc(CNC[C@@H](O)[C@@H](N)Cc2ccccc2)c1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CC(C)(C)OC(=O)NCc1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cncc(C(C)C)c2)c1
Reaction time: 1 h
Yield: 69 %

Procedure:
EDCI.HCl (0.175 g, 0.915 mmol, 1.1 eq) and HOBT.H2O (0.124 g, 0.915 mmol, 1.1 eq) were added to a stirred solution of 3-(methoxycarbonyl)benzoic acid in 5 ml anhydrous CH2Cl2 at 0° C. under Ar. In a separate flask (2R,3S)-3-amino-1-((5-isopropylpyridin-3-yl)methylamino)-4-phenylbutan-2-ol (0.3118 g, 0.832 mmol, 1.1 eq) in 3 ml anhydrous CH2Cl2 under Ar was treated with DIPEA (1.2 ml, 0.86 g, 6.66 mmol, 8 eq). After both solutions had stirred for 1 h, the active ester was treated with the free-base amine. The reaction was stirred at 0° C. to room temperature overnight. The solvent was removed in vacuo. The residue was partitioned between EtOAc/H2O and the layers were separated. The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo. Purification via flash chromatography yielded 0.274 g (0.58 mmol, 69% yield) of methyl 3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoate.
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[C:9](OC)(OC)(OC)[CH2:10][CH2:11][CH3:12]>>[CH2:10]([C:9]1[NH:1][C:2]([C:7]#[N:8])=[C:3]([C:4]#[N:5])[N:6]=1)[CH2:11][CH3:12]
Reactant: CCCC(OC)(OC)OC
Reactant: N#C/C(N)=C(/N)C#N
Product: CCCc1nc(C#N)c(C#N)[nH]1
Yield: 78.9 %

Procedure:
Following a procedure similar to that described in Preparation 1, but using 16.0 g of diaminomaleonitrile and 24 g of trimethyl orthobutyrate, 18.7 g of the title compound were obtained as crystals, melting at 141°-144° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].Cl>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([C:20](=[O:21])[CH2:19][Cl:18])=[CH:16][CH:17]=1
Reactant: O=C(Cl)CCl
Reactant: Clc1ccccc1-c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc(-c2ccccc2Cl)cc1
Reaction time: 18 h
Yield: 90.3 %

Procedure:
293.7 g (2.2 mols) of aluminium chloride are introduced in portions to a solution of 377 g (2 mols) of 2-chlorobiphenyl in 160 ml (2 mols) of chloroacetyl chloride and 1,000 ml of methylene chloride. After 18 hours, the reaction mixture is poured onto ice and hydrochloric acid. The organic phase is seperated off, washed, dried over sodium sulphate and concentrated in vacuo by distilling off the solvent. The oil which remains is purified by distillation. 478.7 g (90% of theory) of 4(2-chlorophenyl)phenacyl chloride of melting point 47° C. are obtained.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]2[CH2:14][CH2:15][N:16]([C:17](=[O:39])[CH:18]([NH:25][C:26](=[O:38])[CH:27]([N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH3:30])[CH3:28])[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:6]12)=[O:4].[OH-].[Na+]>CO>[C:34]([O:33][C:31]([N:29]([CH3:30])[CH:27]([CH3:28])[C:26]([NH:25][CH:18]([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[C:17]([N:16]1[CH:6]2[CH:7]([N:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:9][CH:5]2[C:3]([OH:4])=[O:2])[CH2:14][CH2:15]1)=[O:39])=[O:38])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C3CCCCC3)C12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)O)CN2S(C)(=O)=O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of 20 (362 mg, 0.63 mmol) in MeOH (10 mL) was treated with 1M NaOH (2 mL) at ambient temperature. After 1 h, the solution was concentrated and diluted with EtOAc and 1M HCl. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed successively with 1M HCl, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 21 as a yellow-colored foam (278 mg) which was used without further purification.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:37])=[C:7]2[C:12](=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]3[S:32][C:31](=N)[NH:30][C:29]3=[O:34])=[CH:25][CH:24]=1)([CH3:19])[CH2:9][CH2:8]2)(=O)C.Cl.[OH2:39]>COCCO>[OH:4][C:5]1[C:6]([CH3:37])=[C:7]2[C:12](=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH:28]3[S:32][C:31](=[O:39])[NH:30][C:29]3=[O:34])=[CH:35][CH:36]=1)([CH3:19])[CH2:9][CH2:8]2
Reactant: O
Reactant: COc1c(OC(C)=O)c(C)c2c(c1OC)OC(C)(CCOc1ccc(CC3SC(=N)NC3=O)cc1)CC2
Agent: Cl
Solvent: COCCO
Product: COc1c(O)c(C)c2c(c1OC)OC(C)(CCOc1ccc(CC3SC(=O)NC3=O)cc1)CC2

Procedure:
560 mg of 5-{4-[2-(6-acetoxy-7,8-dimethoxy-2,5-dimethylchroman-2-yl)ethoxy]benzyl}-2-iminothiazolidin-4-one (prepared as described in Example 7) were added to a mixture of 7 ml of concentrated hydrochloric acid, 2.5 ml of water and 10 ml of ethylene glycol monomethyl ether, and the mixture was heated under reflux for 13 hours. The reaction mixture was then processed and purified as described in Example 1(a), except that the crude product, in the form of an oil, was purified by column chromatography through silica gel eluted with a 9:1 by volume mixture of chloroform and ethyl acetate, to give the title compound.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2].C[N:38](C=O)C.N>C(O)C>[C:1]([N:3]=[C:4]([NH2:38])[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2]
Reactant: CSC(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Solvent: CCO
Product: Cn1cc(C2=C(c3cn(CCCNC(N)=NC#N)c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
100 mg of the product of Example 50 were heated with 30 ml of ethanol, 2 ml of DMF and 40 ml of a saturated solution of ammonia in ethanol at 100° C. for 16 hours. The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with 1% methanol in dichloromethane to give 10 mg of 3-[1-[3-(2-cyanoguanidino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 168°-170° C.