Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[F:56][C:57]1[CH:58]=[C:59]([CH2:65]O)[S:60][C:61]=1[CH2:62][CH2:63][CH3:64]>C1COCC1>[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH2:65][C:59]3[S:60][C:61]([CH2:62][CH2:63][CH3:64])=[C:57]([F:56])[CH:58]=3)=[CH:53][CH:54]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCc1sc(CO)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1cnc(-c2ccc(OCc3cc(F)c(CCC)s3)cc2)nc1

Procedure:
A fully reacted mixture of equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in THF is admixed with equimolar amounts of 4-(5-undecyl-pyrimidin-2-yl)phenol and 4-fluoro-5-propyl-thiophen-2-yl-methanol (prepared by LiAlH4 reduction of methyl 4-fluoro-5-propyl-thiophene-2-carboxylate). After 24 h at room temperature the mixture is evaporated to dryness under reduced pressure. Purification by chromatography (silica gel, dichloromethane) and recrystallization affords the target compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=2)[NH:6][CH:5]=1)#[N:2].CN.[C:21](OCC)(=O)C.CC(O)C.O>C(O)C.[Pd]>[CH3:21][NH:2][CH2:1][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][NH:14][S:15]([CH3:18])(=[O:16])=[O:17])[CH:11]=2)[NH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)NCc1ccc2[nH]cc(CC#N)c2c1
Agent: [Pd]
Agent: CN
Solvent: CCO
Solvent: CC(C)O
Solvent: O
Product: CNCCc1c[nH]c2ccc(CNS(C)(=O)=O)cc12

Procedure:
A solution of N-[[3-(cyanomethyl)-1H-indol-5-yl]methyl]methanesulphonamide (0.04 g) in absolute ethanol (10 ml) containing methylamine in ethanol, (33%, 0.5 ml) was hydrogenated at room temperature and pressure over palladium on charcoal (10%, 50% aqueous paste, 0.05 g). After 60 h TLC Silica, ethyl acetate/2-propanol/water/0.88 ammonia (25:15:2) showed one major basic spot Rf 0.4, identical to authentic product (see Example 2)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[N:11]=2)[CH2:3][CH2:2]1.[CH2:21]=O>C(O)(=O)C.CO.O1CCCC1>[CH3:21][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[N:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2csc(C3CCNCC3)n2)cc1
Reactant: C=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(c2nc(-c3ccc(C(=O)O)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-Piperidin-4-yl-thiazol-4-yl)-benzoic acid (1 mmol) in acetic acid (0.5 mL), methanol (3 mL) and tetrahydrofurane (4.5 mL) was added formaldehyde (aq. 37%, 300 mL) and polystyrene bound cyanoborohydride (2.36 mmol/g, 900 mg). The slurry was then agitated for 16 hours at room temperature. The slurry was then filtered and the resin washed with methanol (2 mL). The solution was concentrated to dryness in vacuo. m/z=303.1 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH2:14])=[O:13])[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].Br[C:16]1[O:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:14][C:16]2[O:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=2)=[O:13])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(N)=O)oc1C(C)C
Reactant: COC(=O)c1ccc(Br)o1
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)o1
Yield: 48.9 %

Procedure:
4,5-Diisopropylfuran-2-carboxamide (55 mg, 0.282 mmol) and methyl 5-bromofuran-2-carboxylate (116 mg, 0.566 mmol) were coupled. The reaction mixture was treated in a conventional manner, and the resultant was purified by silica gel chromatography [hexane-ethyl acetate (9:1)] and recrystallized to obtain methyl 5-[(4,5-diisopropylfuran-2-carbonyl)amino]-2-furancarboxylate (44 mg, 49%) and the collected starting material (26 mg, 47%) as colorless needles.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[S:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:7]2=[N:6][CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C:50]1[CH:51]=[C:52]([NH:57][C:58](=[O:70])[C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([C:68]#[N:69])([CH3:67])[CH3:66])[CH:60]=2)[CH:53]=[CH:54][C:55]=1[CH3:56]>CN(C=O)C>[C:68]([C:65]([C:61]1[CH:60]=[C:59]([CH:64]=[CH:63][CH:62]=1)[C:58]([NH:57][C:52]1[CH:53]=[CH:54][C:55]([CH3:56])=[C:50]([NH:49][C:13]([C:11]2[S:10][C:8]3=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][N:6]=[C:7]3[CH:12]=2)=[O:15])[CH:51]=1)=[O:70])([CH3:67])[CH3:66])#[N:69]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: CCOc1cnc2cc(C(=O)O)sc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Temperature: 80 °C
Yield: 7.1 %

Procedure:
A solution of 97 (0.085 mmol, 18.29 mg), N,N-diisopropylethylamine (0.426 mmol, 0.070 ml, 55.1 mg) and HATU (0.128 mmol, 48.6 mg) in DMF (1 mL) was stirred for 5 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 5 (0.085 mmol, 25 mg) was added and stirred at 80° C. over the weekend. The reaction mixture was quenched in citric acid solution and extracted with ethyl acetate (2×). Organic layer was washed with brine, dried and concentrated under reduced pressure. The crude compound was purified with HPLC to give the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-ethoxythieno[2,3-b]pyrazine-6-carboxamide 98 (3 mg, 7%). NMR (400 MHz, CDCl3) 1.48 (t, 3H), 1.78 (s, 6H), 2.36 (s, 3H), 4.51 (q, J=7.0 Hz, 2H), 7.24 (m, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.72 (t, J=7.8 Hz, 2H), 7.79 (m, 2H), 7.91 (s, 1H), 7.98 (m, 2H), 8.16 (d, J=2 Hz, 1H), 8.32 (s, 1H). (m/z)=501 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)([CH:13]=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].O.O.P([O-])(O)(O)=[O:26].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>O1CCCC1.O>[CH:16]1([CH2:15][C:11]2([C:13]([OH:26])=[O:14])[CH2:12][CH:7]3[CH2:6][N:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:22])[CH2:9][CH:8]3[CH2:10]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=P([O-])(O)O
Reactant: CN(C)C(=O)N1CC2CC(C=O)(CC3CCCCC3)CC2C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)N1CC2CC(CC3CCCCC3)(C(=O)O)CC2C1
Temperature: 0 °C
Yield: 99.8 %

Procedure:
5-Cyclohexylmethyl-5-formyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 15b (0.713 g, 2.33 mmol) was dissolved in the solvent mixture of 60 mL of tetrahydrofuran and 30 mL of water. Upon cooling to 0° C., sodium dihydrogenphosphate dihydrate (1.09 g, 6.99 mmol), sodium chlorite (0.79 g, 6.99 mmol) and 2-methyl-2-butene (0.62 mL, 7.0 mmol) were added. The reaction mixture was reacted at 0° C. for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated to remove tetrahydrofuran and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-cyclohexylmethyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 15c (0.75 g, yield 100%) as a yellow solid.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][OH:15])[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][O:15][S:23]([CH3:26])(=[O:25])=[O:24])[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2csc(CO)n2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2csc(COS(C)(=O)=O)n2)OCCO1
Temperature: 0 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-yl]-methanol (745 mg, 3.70 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.67 mL, 4.79 mmol) followed by DMAP (46 mg, 0.37 mmol) and Ms-Cl (0.37 mL, 4.67 mmol). After stirring at 0° C. for 1 h30, the reaction was quenched with water (5 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude methanesulfonic acid 4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl ester as a yellow oil. The crude material (580 mg) was dissolved in acetone (12 mL) under inert atmosphere (N2). 4-Nitro-1H-pyrazole (264 mg, 2.08 mmol) was added followed by K2CO3 (1.45 g, 10.38 mmol) and TBA bromide (134 mg, 0.41 mmol). The reaction mixture was stirred overnight at rt and concentrated to dryness. The residue was partitioned between water (10 mL) and EA (20 mL). The layers were separated and the aq. layer extracted with EA (2×30 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (10:1 to 2:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:2 hept-EA)=0.41. LC-MS-conditions 02: tR=0.86 min, [M+H]+=297.35.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (140 mg, 0.40 mmoles) and phenyl isocyanate (72 mg, 0.61 mmoles), the title compound was isolated as a white solid. The product was purified by Silica gel column chromatography by eluting it with ethyl acetate. Yield: 0.128 g (68%) (M+H)=462.3
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: NCCc1ccccn1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCc2ccccn2)cc1
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
4-geranyloxybenzoic acid(1.37 g) was dissolved in chloroform(30 ml) and triethylamine(1.53 ml), and then diphenylphosphinic chloride(1.05 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 2-(2-aminoethyl)pyridine(0.67 g) added thereto, was stirred for 1.5 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.39 g of the aimed compound.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].CCN=C=N[CH2:13][CH2:14][CH2:15][N:16]([CH3:18])C.C1C=CC2N(O)N=NC=2C=1.N1CCCC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:16]1([C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[CH2:15][CH2:14][CH2:13][CH2:18]1
Reactant: C#CCCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCNC1
Product: C#CCCC(=O)N1CCCC1
Reaction time: 2 h
Yield: 80.4 %

Procedure:
4-Pentynoic acid (500 mg, 5.1 mmol), EDCI (1.56 g, 7.7 mmol) and HOBt (1.411 g, 10.2 mmol) were dissolved in 20 mL of DCM under inert atmosphere. A mixture of pyrrolidine (850 uL, 10.2 mmol) and DIPEA (4.5 mL, 25.5 mmol) in 3 mL DCM was added and the mixture was stirred for 2 h. The mixture was quenched with 25 mL 10% citric acid, stirred for 5 min., the organic layer was collected and the aqueous layer was extracted with 2×20 mL DCM. The combined organic layers were washed with 20 mL 10% citric acid. The DCM layer was washed with 20 mL saturated sodium bicarbonate, 20 mL brine and dried over sodium sulfate. The filtrates were concentrated and the residue was adsorbed on silica gel and chromatographed on silica gel (12 g) using 0→20% EtOAc-DCM to give 620 mg of 1-(pyrrolidin-1-yl)pent-4-yn-1-one.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][C@@H:10]([C:21]([OH:23])=O)[NH:11][C:12](=[O:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][C:6]=1[Cl:26])[CH:2]=[CH2:3].Cl.[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32].C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.C(Cl)(Cl)Cl>[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:21](=[O:23])[C@H:10]([CH2:9][C:8]1[CH:24]=[CH:25][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[C:6]([Cl:26])[CH:7]=1)[NH:11][C:12](=[O:20])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CCOc1ccc(C[C@H](NC(=O)Cc2ccccc2)C(=O)O)cc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CCOc1ccc(C[C@H](NC(=O)Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)OC)cc1Cl
Reaction time: 8 h

Procedure:
4-Allyloxy-3-chloro-phenylacetyl-(L)-phenylalanine (1.87 g) was dissolved in dry tetrahydrofuran (10 ml). To the solution was added (L)-phenylalanine methyl ester hydrochloride in dry chloroform (10 ml) containing dry triethylamine (0.7 ml). DCC (1.02 g) was added and the reaction mixture was stirred overnight.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20](=[O:29])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[N:41]1([C:3]2[N:8]=[C:7]([NH:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=3)[C:6]([C:20](=[O:29])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:5][N:4]=2)[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ccccn2)cc1Cl
Reactant: C1CNCCN1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(N3CCNCC3)ncc2C(=O)NCc2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine (prepared in Example 80) 150.0 mg in chloroform 5.0 ml is treated with m-chloroperbenzoic acid (80%) 85.6 mg at 0° C. for 30 minites. Piperazine 0.263 g is added thereto and the mixture is stirred at room temperature overnight. To the reaction mixture is added ethyl acetate and an aqueous saturated sodium hydrogen carbonate solution, and the organic layer is separated. The organic layer is washed with an aqueous saturated sodium hydrogen carbonate solution, water and a saturated brine, dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo. The residue is purified with silica gel chromatography (solvent; ethyl acetate) to give 2-(1-pyperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine as a colorless amorphous solid, 128.4 mg.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6]3=[N:13][C@@H:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[N:5]3[C:4]=2[N:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].ClC[CH2:27][C:28]([CH3:33])([CH3:32])[C:29]([O-:31])=[O:30]>CN(C=O)C>[CH3:1][C:2]1[N:10]([CH2:19][O:31][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6]3=[N:13][C@@H:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[N:5]3[C:4]=2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc2c([nH]1)C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12
Reactant: CC(C)(CCCl)C(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c(n1COC(=O)C(C)(C)C)C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12

Procedure:
Treat 5,6a(R),7,8,9,9a(S)-hexahydro-2,5-dimethylcyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one from Example 19a (0.28 g, 1.1 mmol) in DMF with (4 ml) with potassium carbonate (0.24 g) and chloromethylpivalate (0.2 ml, 1.4 mmol) at 35° C. for 6 hr. Cool and filter the reaction mixture. Partition the filtrate with brine and ethyl acetate: THF 1:1. Dry and concentrate the organic layer to give the title compound as a powder.
Reaction SMILES: [CH2:1]([N:5]([CH2:39][CH2:40][CH2:41][CH3:42])[C:6]([C:8]1[N:9]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=2[C:27]([N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:28])[N:11]([CH2:13][C:14]([OH:16])=O)[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:43][N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:1]([N:5]([CH2:39][CH2:40][CH2:41][CH3:42])[C:6]([C:8]1[N:9]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=2[C:27]([N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:28])[N:11]([CH2:13][C:14]([NH:44][CH3:43])=[O:16])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)C(=O)c1cn(CC(=O)O)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1cn(CC(=O)NC)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-(dibutylcarbamoyl)-2-(4-(methoxycarbonyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-imidazol-1-yl)acetic acid (180 mg, 0.31 mmol) in dry DMF (5 mL) was added HATU (595 mg, 1.56 mmol), methylamine (Aldrich, 78 μL, 1.56 mmol, 2.0 M in THF) and diisopropylethyl amine (544 μL, 3.13 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature over 30 min and stirring was continued for 16 h. The reaction mixture was diluted with water, and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give crude product. The crude material was purified by flash chromatography (gradient from 20 to 50% EtOAc/hexanes) to provide (85 mg, 46%). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.22-8.19 (m, 1H), 8.10 (dd, J=6.0, 1.6 Hz, 1H), 7.58 (s, 0.5H), 7.56-7.52 (m, 1H), 7.50 (s, 0.5H), 7.36-7.10 (m, 3.5H), 6.94 (d, J=7.6 Hz, 0.5H), 4.76 (br s, 1H), 4.65 (br s, 3H), 3.98 (s, 3H), 3.97-3.95 (m, 1.5H), 3.73 (t, J=5.6 Hz, 1.5H), 3.60-3.30 (m, 3H), 3.00-2.85 (m, 2H), 2.65 (s, 1.5H), 2.64 (s, 1.5H), 1.47-1.24 (m, 6H), 0.96-0.84 (m, 5H), 0.80 (t, J=7.4 Hz, 1.5H), 0.60 (t, J=7.4 Hz, 1.5H); MS(ESI+) m/z 588.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7]2[S:8][CH2:9][CH2:10][CH2:11][C:6]=2[C:5]2[C:12]([OH:25])=[CH:13][C:14]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])=[CH:15][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH3:43][CH:44]([CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)[C:45](O)=[O:46].C(Cl)[Cl:57]>CO.C(Cl)(Cl)Cl>[ClH:57].[CH3:26][C:2]1([CH3:1])[C:7]2[S:8][CH2:9][CH2:10][CH2:11][C:6]=2[C:5]2[C:12]([O:25][C:45](=[O:46])[CH:44]([CH3:43])[CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)=[CH:13][C:14]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])=[CH:15][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCCS1
Reactant: ClCCl
Reactant: CC(CCN1CCCCC1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)C(C)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCCS1

Procedure:
A combination of 0.5 g. (1.33 mmole) of 1,2-dihydro-5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-3H,5H-thiopyrano [2,3-c][1]benzopyran, 0.30 g. (1.45 mmole) of dicyclohexylcarbodiimide, 0.29 g. (1.33 mmole) of 2-methyl-4-piperidinobutyric acid hydrochloride and 25 ml. of methylene chloride was stirred at room temperature for 16 hours. The reaction mixture was cooled for several hours and the byproduct of dicyclohexylurea was removed by filtration. After removal of the solvent on a rotary evaporator, the residue was combined with 15 ml. of diethyl ether and an additional amount of the dicyclohexylurea was removed by filtration. The solvent was evaporated and the residue thoroughly dried to give 0.40 g. (50%) of beige solid. The sample was pure by thin layer chromatography (10% MeOH/CHCl3), and the infrared spectrum was consistent with the desired product. Anal. Calcd. for C33H52ClNO3S.H2O (MW=596.28) C, 66.44, H, 9.13; N, 2.35; Found: C, 65.84; H, 9.01; N, 2.70.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:5][CH:4]=1.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O>[C:9]([C:7]1[C:6]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:5][CH:4]=[C:3]([CH2:2][O:1][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[N:8]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(c1ccccc1)c1nc(CO)ccc1OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(OCc2ccccc2)c(C(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
116 g of 6-hydroxymethyl-2-benzoyl-3-benzyloxypyridine was dissolved in 450 ml of N,N-dimethylformamide. 100 g of imidazole and 85 g of tert-butyldimethylsilyl chloride was added thereto, followed by stirring at room temperature overnight. The solvent was removed, water was added thereto and the mixture was extracted with ethyl acetate. Further, the organic phase was washed with dilute hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was dried, to give 141 g of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([NH:17][NH2:18])=[O:16])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]2[O:16][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)NN
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(Br)cc2)c1Cc1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid hydrazide (0.142 g, 0.46 mmol) in CH2Cl2 (2.3 mL) at 0° C. was added triethylamine (0.19 mL, 1.37 mmol) and benzoyl chloride (0.05 mL, 0.46 mmol), and the reaction was stirred at room temperature for 3 hours. Toluenesulfonyl chloride (0.088 g, 0.46 mmol) was added, and the reaction was stirred overnight. After aqueous workup, the crude material was purified by silica gel chromatography to give the title compound.