Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:4][C:3]1=2.C[Si]([C:22]#[N:23])(C)C>B(F)(F)F.Cl>[C:22]([C:2]1[C:3]2[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:8]=2[CH2:9][CH2:10][CH:11]=1)#[N:23]
Reactant: COC(=O)COc1ccc2c(c1)CCCC2=O
Reactant: C[Si](C)(C)C#N
Agent: Cl
Agent: FB(F)F
Product: COC(=O)COc1ccc2c(c1)CCC=C2C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 to 3 drops of BF3 -etherate solution are added to 0.1 mol of methyl 5-oxo-5,6,7,8-tetrahydro-naphth-2-yl-oxyacetate and 0.15 mol of trimethylsilyl cyanide, and the mixture is stirred at room temperature for 30 minutes and then at 50° C. for 1 hour. 250 ml of a saturated methanolic hydrogen chloride solution are added to this solution at room temperature and the mixture is stirred for 1 hour. Some of the product precipitates out and is filtered off. A further batch is obtained by evaporating the motor liquor, taking up the residue in CH2Cl2, extracting the mixture twice by shaking with 0.5N NaOH, drying the extract over Na2SO4 and evaporating it and recrystallizing the residue from a little methanol or diisopropyl ether.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][NH:21][CH3:22].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:20][N:21]([CH3:22])[S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CNC
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N(C)C)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (110 mg; 0.33 mmol; 1 eq), is dissolved in DMF (10 ml). Dimethylamine (0.1 ml; 1.65 mmol; 5 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After one hour, the solvents are evaporated to dryness. The crude product is re-dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is precipitated in a mixture of DCM and diethyl ether, affording after filtration, Compound (18) as a yellow powder (52 mg; 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH3:43][C:44]1[N:45]=[C:46]([CH:49]([NH2:51])[CH3:50])[S:47][CH:48]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:51][CH:49]([C:46]2[S:47][CH:48]=[C:44]([CH3:43])[N:45]=2)[CH3:50])=[O:41])=[CH:18][C:17]=1[F:23]
Reactant: Cc1csc(C(C)N)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4nc(C)cs4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-methyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (29 mg, yield 63%).
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH3:30][O:31][CH:32]1[C:37](=O)[CH2:36][CH2:35][O:34][CH2:33]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH:11][CH:37]2[CH2:36][CH2:35][O:34][CH2:33][CH:32]2[O:31][CH3:30])[CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Reactant: COC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-(4-[6-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (110 mg, 0.24 mmol), 3-methoxytetrahydro-4H-pyran-4-one (80 mg, 0.61 mmol), and triethylamine (0.16 mL, 1.2 mmol) in methylene chloride (8 mL) was added sodium triacetoxyborohydride (190 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1) to give 123 mg of desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give isomer 1 (45 mg after converting to TFA salt) and isomer 2 (35 mg after converting to TFA salt). LCMS calculated for C25H37F3N4O3: (M+H) 498.2; found 498.2 for both isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:49][O:50][C:51](=[O:65])[C@H:52]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([C:63]#[N:64])[CH:58]=1)[C@H:53]([NH2:55])[CH3:54]>CN(C=O)C.CCOC(C)=O>[CH3:49][O:50][C:51](=[O:65])[C@H:52]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([C:63]#[N:64])[CH:58]=1)[C@H:53]([NH:55][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:17][CH:16]=1)[CH3:54]
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cn1
Reactant: COC(=O)[C@H](Cc1cccc(C#N)c1)[C@@H](C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1cccc(C#N)c1)[C@@H](C)NC(=O)c1ccc(-c2ccc(OC)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a stirred solution of 4-(6-methoxy-pyridin-3-yl)-benzoic acid (0.67 g, 2.54 mmol) in DMF (5 mL) is added DIPEA (0.44 mL, 2.54 mmol), TBTU (0.91 g, 2.54 mmol) and 2(R)-(3-Cyano-benzyl)-3(R)-amino-butyric acid methyl ester (0.59 g, 2.54 mmol). The solution is stirred overnight at room temperature. The reaction is diluted with EtOAc and washed with saturated sodium bicarbonate (3×), brine, dried over MgSO4, filtered and concentrated. The crude product is purified by flash chromatography (50% EtOAc/hexane to 60% EtOAc/hexane) to give the product as a white solid (0.83 g, 1.87 mmol). 1H NMR (CDCl3, 300 MHz) δ8.43 (d, 1H), 7.92 (d, 2H), 7.83 (dd, 1H), 7.63 (d, 1H), 7.30-7.55 (m, 4H), 6.87 (d, 1H), 4.42-4.53 (m, 1H), 3.98 (s, 3H), 3.66 (s, 3H), 2.85-3.08 (m, 3H), 1.28 (d, 3H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([O:29][CH3:30])[CH:23]=2)CC2CCCC2)=[O:14])=[N:9][CH:8]=1)C.[CH:32]1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)[CH2:36][CH2:35][CH2:34][CH2:33]1.[CH:61]1(CNC2C=CC(F)=C(OC)C=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:32]1([N:15]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([O:29][CH3:30])[CH:23]=2)[C:13](=[O:14])[N:12]([CH3:61])[C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:31])=[CH:8][N:9]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: COc1cc(NCC2CCCC2)ccc1F
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(OC)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1cc(N(C(=O)N(C)c2ncc(SCC(=O)O)s2)C2CCCC2)ccc1F

Procedure:
The title compound was prepared via {2-[3-(4-fluoro-3-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-fluoro-3-methoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2([NH:19]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH2:12]1)=O)C1C=CC=CC=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43]C=1F)[N:41]([C@@H:46]1[CH2:48][C@@H:47]1[F:49])[CH:40]=[C:39]([C:50]([OH:52])=[O:51])[C:38]2=[O:53].[OH-].[Na+]>CO.[C].[Pd]>[NH2:19][C:16]1([C@@H:13]2[CH2:14][CH2:15][N:11]([C:9]3[CH:43]=[C:42]4[C:37]([C:38](=[O:53])[C:39]([C:50]([OH:52])=[O:51])=[CH:40][N:41]4[C@@H:46]4[CH2:48][C@@H:47]4[F:49])=[CH:36][C:35]=3[F:34])[CH2:12]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)c(F)cc2c1=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: NC1([C@@H]2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4[C@@H]3C[C@@H]3F)C2)CC1
Reaction time: 2 h
Yield: 77 %

Procedure:
A 322 mg (0.89 mmol) portion of (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine was dissolved in 10 ml of methanol to which was subsequently added 100 mg of 5% palladium-carbon to carry out 2 hours of hydrogenation under normal pressure with warming by an infrared lamp. After completion of the reaction, 5% palladium-carbon was removed by filtration and methanol was evaporated. The resulting residue was dissolved in 5 ml of acetonitrile to which were subsequently added 0.5 ml of triethylamine and 113 mg (0.4 mmol) of 6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, followed by 18 hours of heating under reflux. After completion of the reaction, the reaction solution was spontaneously cooled to collect the thus formed crystals by filtration. With cooling in an ice bath, to the thus obtained crystals was added dropwise 5 ml of concentrated hydrochloric acid, followed by 30 minutes of stirring at the same temperature. After completion of the reaction, the reaction solution was adjusted to pH 12 with sodium hydroxide aqueous solution and then to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (50 ml×3). The organic layers were combined and dried on sodium sulfate, and then the solvent was evaporated. Thereafter, the resulting residue was recrystallized from liquid ammonia-ethanol to yield 120 mg (77%) of the title compound.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:30]=[CH:29][C:15]([C:16]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23]CC)=[O:22])=[O:17])=[CH:14][C:13]=1[CH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Li+]>CC(C)=O.O>[CH2:1]([O:11][C:12]1[CH:30]=[CH:29][C:15]([C:16]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([OH:23])=[O:22])=[O:17])=[CH:14][C:13]=1[CH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1Cc1nnn[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)O)c2)cc1Cc1nnn[nH]1
Reaction time: 6 h
Yield: 8.6 %

Procedure:
A mixture of 580 mg of the product from Example 2 and 280 mg of lithium hydroxide in 10 ml of acetone and 1 ml of water were stirred for 6 hours. The mixture was concentrated in vacuo and the resulting residue was partitioned between diethyl ether and water. The layers were separated and the aqueous layer was extracted with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate and concentrated to dryness. The residue was crystallized from hexane/ethyl acetate to provide 47 mg of the title product, m.p. 147°-150° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10]C)=O)=[N:4][CH:5]=[CH:6][N:7]=1.[NH3:12]>CO>[NH2:1][C:2]1[C:3]([C:8]([NH2:12])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1nccnc1N
Reactant: N
Solvent: CO
Product: NC(=O)c1nccnc1N
Temperature: 112.5 °C
Yield: 97.7 %

Procedure:
A suspension of methyl 3-aminopyrazine-2-carboxylate (5 g, 32.6 mmol) and 150 mL of dry methanol saturated with anhydrous ammonia were heated in an autoclave at 110-115° C. for 24 h. Concentration and filtration afforded 3-aminopyrazine-2-carboxamide (4.4 g, 97.7% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7](N1CCC(NCC3C4C=CC=CC=4CCC4C=CC=CC3=4)CC1)=[N:8][C:9]=2[NH:13][CH2:14][CH:15]=[CH2:16])[CH:2]=[CH2:3].C(N)C=C.[Cl:44]C1N=C2C(N=CN2CC=C)=C(Cl)N=1>C(O)C>[Cl:44][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[CH:12][N:4]2[CH2:1][CH:2]=[CH2:3])=[C:9]([NH:13][CH2:14][CH:15]=[CH2:16])[N:8]=1
Reactant: C=CCn1cnc2c(Cl)nc(Cl)nc21
Reactant: C=CCNc1nc(N2CCC(NCC3c4ccccc4CCc4ccccc43)CC2)nc2c1ncn2CC=C
Solvent: C=CCN
Solvent: CCO
Product: C=CCNc1nc(Cl)nc2c1ncn2CC=C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9-allyl-6-allylamino-2-{4-[(10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5-yl)methylamino]piperidino}purine ##STR14## 0.75 ml of allylamine is added to a solution of 1.15 g of 2,6-dichloro-9-allylpurine in 15 ml of ethanol and the mixture is stirred for 1 hour at room temperature and then heated at 50° C. for 30 minutes. After evaporation of the solvent, the mixture is taken up in CH2Cl2 -H2O, decanted, and the solvent is evaporated. The residue is recrystallised from ethanol. 1 g of 2-chloro-6-allylamino-9-allylpurine, melting at 110°-112° C. is obtained. 0.85 g of that compound is dissolved in 20 ml to butanol, 1.04 g of 4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]-piperidine (oil), 0.5 g of K2CO3 and 0.1 g of potassium iodide are added to the solution obtained, and the mixture is heated at reflux for 10 hours. The reaction mixture is then concentrated and the residue is taken up in CH2Cl2 -H 2 O. The mixture is decanted, the organic phase is then evaporated, and the residue is chromatographed using ethyl acetate as eluant. 0.6 g of 9-allyl-6-allylamino-2-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl) methylamino]piperidino}-purine is isolated in the form of crystals melting (cap) at 142°-144° C. The 9-allyl-2,6-dichloropurine used as starting material was prepared by reacting allyl alcohol and 2,6-dichloropurine in tetrahydrofuran according to the Mitsunobu method. The amine used as starting material was prepared by debenzylation of the corresponding piperidine melting at 78°-81° C., which was itself prepared by reductive alkylation with NaBH3CN, in methanol, of a mixture of 1-benzylpiperidone and (10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamine hydrochloride melting (cap) at 275°-280° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[N:12]=[C:11]2[NH:13][C:14](=[O:27])[N:15]([C:17]3[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=3[CH3:26])[CH2:16][C:10]2=[CH:9][N:8]=1)(=[O:6])=[O:5].I[CH3:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:3][S:4]([C:7]1[N:12]=[C:11]2[N:13]([CH3:29])[C:14](=[O:27])[N:15]([C:17]3[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=3[CH3:26])[CH2:16][C:10]2=[CH:9][N:8]=1)(=[O:5])=[O:6]
Reactant: CI
Reactant: Cc1ccc([N+](=O)[O-])cc1N1Cc2cnc(S(C)(=O)=O)nc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1N1Cc2cnc(S(C)(=O)=O)nc2N(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To the suspension of NaH (60% dispersion in mineral oil, 139 mg, 3.5 mmol) in DMF is added 7-methanesulfonyl-3-(2-methyl-5-nitro-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (1.15 g, 3.2 mmol), prepared as in Reference 1, at 0° C. When H2 evolution has ceased, iodomethane (0.99 ml, 15.8 mmol) is added and the reaction mixture is stirred for 3 hours at room temperature. The mixture is diluted with ethyl acetate, and washed with 5% aqueous Na2S2O3 solution to remove DMF. The organic layer is dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by flash column chromatography (SiO2, EtOAc/hexane=1/1) to give 7-methanesulfonyl-1-methyl-3-(2-methyl-5-nitro-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.85 g, 70%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:20]=[N:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[C:28](N=C(N(C)C)N(C)C)([CH3:31])([CH3:30])[CH3:29].BrCC(C)C>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:19]3[CH:20]=[N:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])[CH2:29][CH:28]([CH3:31])[CH3:30])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: Cc1cc(C)c(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)cn1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: CC(C)CBr
Product: Cc1cc(C)c(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-(4,6-dimethyl-3-pyridinyl)benzenesulfonamide (100 mg, 0.258 mmol) and 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (44.2 mg, 0.258 mmol) were dissolved in acetonitrile (1 mL). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.028 mL, 0.258 mmol) was added. The reaction was stirred at room temperature for 20 hours, then additional 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (44.2 mg, 0.258 mmol) and 1-bromo-2-methylpropane (0.028 mL, 0.258 mmol) were added. The reaction was heated to 60° C. and stirred for a further 2 hours. The solvent was removed in vacuo and the residue was partitioned between water (5 mL) and dichloromethane (5 mL). The organic layer was separated, concentrated and purified by mass directed autoprep (formic acid modifier). The required fractions were combined and concentrated to provide the title compound (17 mg) as a colourless oil. LCMS (2 min, formic) Rt 1.04 mins, m/z (ES+) 444 (M+H).
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:15]3[CH2:16][CH:12]([CH2:13][NH:14]3)[CH2:11][CH:10]=2)[CH:4]=1.C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.CO.O1CCOCC1>[ClH:1].[ClH:1].[CH3:19][N:14]1[CH2:13][CH:12]2[CH2:16][CH:15]1[C:9]([C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)=[CH:10][CH2:11]2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C1=C(c2cccnc2)C2CC(C1)CN2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CC2CC=C(c3cccnc3)C1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-(3-pyridinyl)-6-azabicyclo[3.2.1]oct-3-ene dihydrochloride (90 mg, 0.35 mmol) in 15 mL of dichloromethane was added a solution of formaldehyde (37% aqueous, 0.15 mL, ˜1.8 mmol). With vigorous stirring, solid sodium triacetoxyborohydride (300 mg, 1.4 mmol) was added in two portions. The reaction was allowed to stir overnight at ambient temperature. The reaction mixture was quenched by the addition of a sodium hydroxide solution (10% aqueous, approximately 1 mL), and the whole extracted with dichloromethane (2×10 mL). The organic extracts were washed successively with water and brine (10 mL each), and dried over sodium sulfate. Filtration and removal of solvent in vacuo gave a residue, which was dissolved in a small volume of methanol and treated with approximately 1 mL of 4M HCl in dioxane. The resulting solution was concentrated in vacua, and the residue taken up in a minimum amount of warm isopropanol. After cooling briefly, ether was added to the point of cloudiness, and the solution cooled slowly to ambient temperature. A sticky solid precipitate formed which resisted crystallization. Solvents were removed in vacuo, leaving the product as a hygroscopic, gummy mass (30 mg, 32%).
Reaction SMILES: C1(C[O:8][P:9]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N:44]2C(=O)C3=CC=CC=C3C2=O)([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)C=CC=CC=1.[OH2:55].NN>O1CCOCC1.C1(C)C=CC=CC=1>[C:14]1([CH2:13][O:55][N:11]([PH:9]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])=[O:8])[C@H:12]([C:20]([NH:22][C@H:23]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NP(=O)(CCCCCCN1C(=O)c2ccccc2C1=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: NN
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)N(OCc1ccccc1)[PH](=O)CCCCCCN)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of N-[N-[(phenylmethoxy)(6-phthalimidohexyl)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester in dioxane is treated with hydrazine hydrate and stirred at room temperature under argon. After 24 hours, the mixture is diluted with toluene and the solvents decanted and evaporated to dryness. The residue is purified by extraction and flash chromatography to give N-[(phenylmethoxy)[(6-aminohexyl)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12]CC2C=CC=CC=2)[C:9]([S:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][N:7]=1)(=[O:3])[CH3:2]>O1CCOCC1.O.[Pd]>[C:1]([O:4][CH2:5][C:6]1[NH:7][CH:8]=[C:9]([S:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:10](=[O:12])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(OCc2ccccc2)c(SC(C)(C)C)cn1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCc1cc(=O)c(SC(C)(C)C)c[nH]1
Yield: 100.6 %

Procedure:
A solution of (5-[(1,1-dimethylethyl)thio]-4-[(phenylmethyl)oxy]-2-pyridinyl}methyl acetate (6 g) in 1,4-dioxane/water (100 ml/50 ml) was hydrogenated at atmospheric pressure with 10% palladium on charcol (7 g) overnight. Filtration and evaporation afforded a white solid (4.46 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.CO.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[CH:30]1([C:33]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:15]=[CH:16][C:17]=2[CH3:18])[N:5]=3)=[O:34])[CH2:32][CH2:31]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc2nc(N)sc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of benzyl {3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}carbamate (25.1 g, 61.9 mmol) in pyridine (200 mL) was added cyclopropanecarbonyl chloride (9.47 mL, 105 mmol) at 0° C., and the mixture was stirred at room temperature for 30 min. Methanol (100 mL) and potassium carbonate (8.55 g, 61.9 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration, and washed successively with methanol (200 mL), water (100 mL), methanol (100 mL) and hexane (100 mL) to give the title compound (23.9 g, 81%) as a white solid.