Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@H:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[NH:31]([C:48]([O:50][CH2:51][CH:52]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:58]2[C:53]1=[CH:54][CH:55]=[CH:56][CH:57]=2)=[O:49])[C@H:32]([C:45](O)=[O:46])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:36][CH:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:31]([C:48]([O:50][CH2:51][CH:52]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:58]2[C:53]1=[CH:54][CH:55]=[CH:56][CH:57]=2)=[O:49])[C@H:32]([C:45]([NH:10][C@H:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:46])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[CH:36][CH:35]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of diisopropylethyl amine (1.19 mL, 3.43 mmol) in DCM (50 mL), was added Lys(Z)OMe (1.13 g, 3.43 mmol). To this solution was added FmocTyr(tBu)OH (1.50 g, 3.26 mmol), then HOBt (0.463 g, 3.43 mmol), and finally EDC.HCl (0.6571 g, 3.43 mmol). This solution was allowed to stir for 8 h at which time the organic solution was washed with 1N HCl (2×20 mL), then saturated NaHCO3 (2×20 mL), and finally H2O (2×20 mL). The organic layer was concentrated in vacuo to yield a white solid (2.34 g, 97.5% yield): 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J=7.53, 2H), 7.55 (m, 2H), 7.40 (t, J=7.45, 2H), 7.38-7.29 (m, 7H), 7.08 (m, 2H), 6.88 (d, J=8.25, 2H), 6.43 (br s, 1H), 5.52 (br s, 1H), 5.15-5.07 (br m, 3H), 4.50 (m, 1H), 4.42 (m, 1H), 4.30 (m, 1H), 4.18 (t, J=6.92, 1H), 3.70 (s, 3H), 3.18-2.95 (m, 4H), 1.85-1.35 (m, 4H), 1.30 (s, 10H), 1.20 (br s, 2H); 13C NMR (125 MHz, CDCl3) δ 163.0, 154.6, 143.9-143.8 (3), 141.46, 136.6, 130.0, 128.7, 128.2, 127.9, 127.3, 125.2, 124.5, 120.2 (2), 67.13, 66.8, 53.6, 52.6, 47.3, 41.0, 37.8, 32.6, 29.4, 29.0 (3), 22.17; HRMS (FAB) m/z calcd for C43H49N3O8 (M+H)+ 736.3598, found 736.3623.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:23]([OH:25])=O)[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:51][C:52]1[S:56][C:55](=[S:57])[NH:54][N:53]=1>>[CH:7]1[C:6]2[CH:5]([CH2:4][O:3][C:1]([NH:18][C@H:19]([C:23]([NH:51][C:52]3[S:56][C:55](=[S:57])[NH:54][N:53]=3)=[O:25])[CH:20]([CH3:22])[CH3:21])=[O:2])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1n[nH]c(=S)s1
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1n[nH]c(=S)s1

Procedure:
Fmoc-Valine (0.68 grams), 1-hydroxybenzotriazole (0.36 grams), dicyclohexylcarbodiimide (0.42 grams) and 5-amino-1,3,4-thiadiazole-2-thione (0.4 grams) were reacted according to the procedures described in Example 1. The resulting product was recrystallized from ethanol-pentane. M.P. 141°-144° C. NMR spectrum (d6 -DMSO) 14.06 (s, 1H), 12.56 (s,1H), 8.00-7.60;7.5-7.2 (m, 9H; NH+aromatics) 4.4-4.0 (m, 4H) 2.2-2.0 (m, 1H), 0.98 (bs, 6H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[C:28](O)(=[O:31])[CH2:29][CH3:30]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (10 mg, 48%), MS (ISP) m/z=388.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.[CH3:15][O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH2:19]>>[CH3:15][O:16][C:17](=[O:21])[CH:18]([NH:19][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[CH3:20]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C(C)N
Agent: Cl
Product: COC(=O)C(C)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5chloro-1H-indole-2-carboxylic acid and DL-alanine methyl ester hydrochloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:47]=[CH:46][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[CH:23]=[CH:24]/[CH:25]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[CH2:26][CH2:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:48][NH:49][C:50]([NH2:52])=[S:51]>C1COCC1.CN(C=O)C>[C:7]([C:11]1[CH:47]=[CH:46][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[CH:23]=[CH:24]/[CH:25]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:48][NH:49][C:50](=[S:51])[NH2:52])=[O:33])=[CH:35][CH:36]=2)=[CH:13][CH:12]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C(=O)O)cc2)Cc2ccc(C#N)cc2)cc1
Reactant: NNC(N)=S
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C(=O)NNC(N)=S)cc2)Cc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.9 mg (0.05 mmol) of oxalyl chloride are slowly added dropwise to a solution of 12.7 mg (0.02 mmol) of 4-[(4E)-5-{2-[(4-tert-butylbenzyl)oxy]phenyl}-3-(4-cyanobenzyl)pent-4-en-1-yl]-benzoic acid from Example 100A in 0.2 ml of dry THF with 1 drop of DMF while cooling in ice. The reaction mixture is stirred at RT for 30 minutes and then concentrated in vacuo, and the residue is coevaporated twice with dichloromethane and then taken up in 0.2 ml of THF. This solution is added dropwise to a solution of 4.2 mg (0.05 mmol) of thiosemicarbazide in 0.25 ml of THF at 0° C. The mixture is stirred at RT for 1 hour and then concentrated, and the residue is reacted without further purification in the next stage.
Reaction SMILES: [C:1]([C:3]1([CH2:18][CH2:19]Br)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1([CH2:18][CH2:19][N:22]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:21])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2]
Reactant: N#CC1(CCBr)c2ccccc2CCc2ccccc21
Reactant: CNCCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc(F)cc1)CCC1(C#N)c2ccccc2CCc2ccccc21

Procedure:
A mixture containing 1-[(5-cyano-10,11-dihydrodibenzo[a,d]cyclohepten-5-yl]-2-bromoethane (3.26 g -- see Preparation 26), N-methyl-4-fluorophenethylamine (1.53 g -- see C.A. 80:P120985y), anhydrous potassium carbonate (2.76 g) and acetonitrile (50 ml) was heated under reflux for 24 hours then concentrated in vacuo. Water (50 ml) was added to the residue and the resulting mixture was extracted with dichloromethane (3×60 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 100%) and then with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a viscous oil, yield, 1.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:20])[C:11](=[O:21])[CH2:10][N:9]=1.C(O[CH:25](OCC)[N:26]([CH3:28])[CH3:27])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:20])[C:11](=[O:21])[C:10](=[CH:25][N:26]([CH3:28])[CH3:27])[N:9]=1
Reactant: CN1C(=O)CN=C(c2ccccc2Cl)c2cc(I)ccc21
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=C1N=C(c2ccccc2Cl)c2cc(I)ccc2N(C)C1=O
Temperature: 130 °C

Procedure:
A mixture consisting of 8 gm of 5-(2'-chloro-phenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepin-2-one and 16 ml of N,N-dimethyl-formamide-diethylacetal was heated for 90 minutes at 130°C. Thereafter, the reaction mixture was allowed to cool, and the crystalline substance which separated out was collected by vacuum filtration and washed with benzene and petroleum ether, yielding the compound named in the heading, which had a melting point of 182°-184°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:24]([C:26]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[CH2:28][CH2:27]1)#[N:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:24]([C:26]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:20][CH2:19]5)=[O:17])[N:14]=4)[N:11]=3)[CH:3]=2)=[O:33])[CH2:27][CH2:28]1)#[N:25]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)cn5n4)c3)c2)CC1
Yield: 46.4 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (170 mg, 0.55 mmol), 3-(1-cyanocyclopropyl)benzoic acid (100 mg, 0.55 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (110 mg, 0.55 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol) and N,N-dimethylformamide (10 mL) as starting materials and in the same manner as in Example 318, the title compound (122 mg, 47%) was obtained as a white powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23]([NH:25][NH2:26])=[O:24].C(O)(=O)C>CCO>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12](=[N:26][NH:25][C:23](=[O:24])[C:22]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:21]=1[F:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCC(=O)c1ccccc1
Reactant: NNC(=O)c1cc(F)ccc1F
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCCC(=NNC(=O)c1cc(F)ccc1F)c1ccccc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(tert-butyldimethylsilanyloxy)-1-phenylbutan-1-one (420 mg, 1.5 mmol) in EtOH (4 mL) was added 2,5-difluorobenzoic acid hydrazide (260 mg, 1.5 mmol) and acetic acid (0.07 mL, 1.2 mmol). After stirring the reaction mixture at 90° C. for 5 hours, more acetic acid (0.1 mL) was added. The mixture was stirred at 90° C. for 40 hours and then concentrated under reduced pressure. The mixture of starting material and product was carried forward without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([CH:45]=[CH:46][CH:47]=2)[NH:17][C:18](=[O:44])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([N:25]2[CH:30]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:29]([C:38]([O:40][CH3:41])=[O:39])=[C:28]([CH3:42])[NH:27][C:26]2=[O:43])=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH:30]2[C:29]([C:38]([O:40][CH3:41])=[O:39])=[C:28]([CH3:42])[NH:27][C:26](=[O:43])[N:25]2[C:23]([NH:22][CH2:21][CH2:20][CH2:19][C:18](=[O:44])[NH:17][C:16]2[CH:45]=[CH:46][CH:47]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:15]=2)=[O:24])=[CH:32][CH:33]=1
Reactant: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)Nc2cccc(C3CCN(C(=O)OC(C)(C)C)CC3)c2)C1c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)Nc2cccc(C3CCNCC3)c2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
Into a solution of methyl 3-{[(4-{3-[1-(tert-butoxycarbonyl)-4-piperidinyl]anilino}-4-oxobutyl)amino]carbonyl}-4-(4-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (40.9 mg, 0.0628 mmol) in dichloromethane (2.00 mL) at 0° C. was slowly added trifluoroacetic acid (71.6 mg, 0.628 mmol). The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in iso-PrOH/CHCl3 (1:3, 10 mL) and basified to pH 11 with 10% KOH solution, washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the desired product (34.6 mg, 99%): 1H NMR (400 MHz, CDCl3) δ 8.00 (m, 3H), 7.67 (s, 1H), 7.35-7.27 (m, 4H), 7.04-6.98 (m, 3H), 6.65 (s, 1H), 3.72 (s, 3H), 3.5-3.48 (m, 2H), 3.20-3.11 (m, 3H), 2.42 (t, 2H, J=7.5 Hz), 2.36 (s, 3H), 2.13-2.06 (m, 2H), 1.97-1.88 (m, 4H); ESMS m/e: 552.3 (M+H)+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:17])[CH:13]=2)[N:8]=1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH3:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:6])[CH:16]=[N:15]2
Reactant: COc1ccc(CNc2cnc3cc(C)ccc3n2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nc(N)cnc2c1
Yield: 86.1 %

Procedure:
N-(2,4-Dimethoxybenzyl)-6-methylquinoxalin-2-amine (0.84 g, 2.72 mmol) was stirred in TFA (10 mL, 130 mmol)/CH2Cl2 (10 mL) at room temperature for 30 min. Solvents were removed on the rotary evaporator. Saturated aqueous Na2CO3 (200 mL) was added to the red residue, which then precipitated a tan solid. The mixture was extracted extensively with DCM. The organic layer was dried over sodium sulfate, concentrated, and dried under vacuum to afford 6-methylquinoxalin-2-amine 2,2,2-trifluoroacetate (640 mg, 2.343 mmol, 86% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[Cl:6][C:7]1[C:17]([Cl:18])=[C:16]([C:19](=[O:24])[C:20](=[CH2:23])[CH2:21][CH3:22])[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11](Cl)=[O:12]>O1CCCC1>[Cl:6][C:7]1[C:17]([Cl:18])=[C:16]([C:19](=[O:24])[C:20](=[CH2:23])[CH2:21][CH3:22])[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:12]
Reactant: NCC(=O)O
Reactant: C=C(CC)C(=O)c1ccc(OCC(=O)Cl)c(Cl)c1Cl
Solvent: C1CCOC1
Product: C=C(CC)C(=O)c1ccc(OCC(=O)NCC(=O)O)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
To a stirring suspension of finely ground glycine (6.01 g, 0.08 mole) in tetrahydrofuran (50 ml) was added, dropwise, the solution of [2,3-dichloro-4-(2-methylenebutyryl)phenoxy]acetyl chloride over a period of 15 minutes. The mixture was stirred at ambient temperature for 2.25 hours and then at reflux for one hour. The mixture was cooled, filtered and washed with tetrahydrofuran. The solid was suspended in water (60 ml), filtered, washed with water and dried to give 7.15 g of N-{[2,3-dichloro-4(2-methylenebutyryl)phenoxy]acetyl}glycine. Upon recrystallization from isopropyl alcohol, the product melted at 201.5°-202.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10]C)[C:5]([Cl:12])=[C:4]([Cl:13])[N:3]=1.N[C:15]1N=C(NCCCC)C(Cl)=C(Cl)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH3:10])[CH3:15])[C:5]([Cl:12])=[C:4]([Cl:13])[N:3]=1
Reactant: CCCNc1nc(N)nc(Cl)c1Cl
Reactant: CCCCNc1nc(N)nc(Cl)c1Cl
Product: CC(C)Nc1nc(N)nc(Cl)c1Cl

Procedure:
In analogous manner to that described in Example 3, 2-amino-4-n-propylamino-5,6-dichloro-pyrimidine and 2-amino-4-n-butylamino-5,6-dichloro-pyrimidine may be produced. Isolation and purification may be effected in conventional manner.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:28])[O:4][CH:5]([CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]([OH:28])[O:4][CH:5]([CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=1
Reactant: CC1=CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC1=CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 3-methyl-5-trityloxymethyl-5H-furan-2-one (1.85 g, 5 mmol, prepared by the method of Lopez-Herrera et. al., J. Carbohydrate Chem. 1994, 13, 767) in toluene (25 mL) under N2 atmosphere at −78° C. was added dropwise with stirring DiBAL (10 mL, 10 mmol, 1M solution in toluene). The addition rate was maintained to keep the temperature of the reaction below −70° C. The reaction was stirred at −78° C. for 2 h and quenched with ethyl acetate (4 mL) at that temperature. The reaction mixture was allowed to warm to room temperature and concentrated under vacuum to dryness. The residue obtained was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexanes to furnish 1.65 g (88%) of 3-methyl-5-trityloxymethyl-2,5-dihydro-furan-2-ol (a mixture of isomers) as a white solid; mp 100-102° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]1([NH:17][OH:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH:11]1([N+:17]([O-:18])=[CH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: ONC1CCCCC1
Reactant: O=CCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: [O-][N+](=CCCc1ccccc1)C1CCCCC1
Yield: 74.3 %

Procedure:
To a mixture of 3-phenylpropionaldehyde (5.0 g, 37.3 mmol, 1.0 equiv.) and CHCl3 (150 ml) was added N-cyclohexylhydroxylamine (4.30 g, 41.0 mmol, 1.1 equiv) and p-TsOH (few crystals) and the resulting mixture was refluxed under nitrogen for 22 h. Removal of the solvent an oil was obtained which was purified by flash chromatography (hexanes: EtOAc 1:1) to give N-cyclohexyl-C-(2-phenylethyl)nitrone (6.41 g, 74.4%) as a white solid, m.p. 97.2° C.: 1H NMR (CDCl3) δ 7.33–7.19 (m, 5H,), 6.69–6.65 (t, 1H, Ar—H), 3.67–3.56 (m, 1H), 2.91–2.78 (m, 4H), 1.97–1.63 (m, 7H), 1.37–1.10 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][NH:3]1.[H-].[Na+].[CH2:14](I)[CH3:15].O>CN(C=O)C>[CH2:14]([N:3]1[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:7][C:2]1=[O:1])[CH3:15]
Reactant: CCI
Reactant: COC(=O)c1ccc(=O)[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)OC)ccc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
Methyl 2-oxo-1,2-dihydropyridine-5-carboxylate (400 mg, 2.61 mmol) obtained in Step 3 was dissolved in DMF (3 mL), and 55% sodium hydride (125 mg, 2.87 mmol) and ethyl iodide (0.230 mL, 2.87 mmol) were added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford methyl 1-ethyl-2-oxo-1,2-dihydropyridine-5-carboxylate (375 mg, 79%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[O:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:12]1([C:4]2([CH2:3][CH2:2][NH:1][C:24](=[O:25])[CH2:23][CH2:22][C:18]3[O:17][CH:21]=[CH:20][CH:19]=3)[CH2:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[O:9]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NCCC1(C2CCCC2)CC(=O)CC(=O)O1
Reactant: O=C(O)CCc1ccco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C1CC(=O)OC(CCNC(=O)CCc2ccco2)(C2CCCC2)C1
Yield: 18.7 %

Procedure:
A solution of 6-(2-Amino-ethyl)-6-cyclopentyl-dihydro-pyran-2,4-dione (90 mg, 0.4 mmol) from Step 5 below, TEA (0.22 mL, 1.6 mmol), 3-furan-2-yl-propionic acid (67 mg, 0.48 mmol) and HATU (182 mg, 0.48 mmol) in DMF (2 mL) was stirred at room temperature overnight. The reaction was purified directly by preparatory HPLC to yield the desired product (26 mg, 19% yield). 1H NMR (CDCl3) δ: 1.27-3.47 (m, 21H), 6.94 (s, 1H), 6.19 (s, 1H), 7.22 (s, 1H). MS (ESI): 346 (M−H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[S:14][C:15]4[N:16]=[CH:17][N:18]=[C:19](SC)[C:20]=4[N:21]=3)=[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:32]1C(C2SC3N=CN=C(SC)C=3C=2)=C(C2C=CC=CC=2)N=C1)C.N>>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[S:14][C:15]4[N:16]=[CH:17][N:18]=[C:19]([NH2:32])[C:20]=4[N:21]=3)=[C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCn1cnc(-c2ccccc2)c1-c1cc2c(SC)ncnc2s1
Reactant: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC3CCCCC3)nc12
Agent: N
Product: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC3CCCCC3)nc12

Procedure:
The title compound was prepared by a similar process to that described for Example 56 but using 2-[1-(cyclohexylmethyl)-4-phenyl-1H-imidazol-5-yl]-7-(methylthio)[1,3]-thiazolo[5,4-d]pyrimidine (Intermediate 79) in place of 6-(1-ethyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 70) and using NH3 gas in place of NH3 solution (0.5 M in dioxane). Solid (160 mg, 25%);
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[Br:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:33](=[O:34])[CH2:32][O:31][C:30]3[CH:36]=[CH:37][C:27]([Br:26])=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:25][CH:24]=3)[S:9][C:10]=2[N:11]=1
Reactant: O=C(O)COc1ccc(Br)cc1
Reactant: Cc1ccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)cc1
Product: Cc1ccc(CCc2nc3c(N4CCN(C(=O)COc5ccc(Br)cc5)CC4)nc(N)nc3s2)cc1
Yield: 47 %

Procedure:
This compound was prepared from 2-(4-methylphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-bromophenoxyacetic acid in a yield of 47%, according to the procedure for the synthesis of example 50.
Reaction SMILES: C(S[C:4]1[NH:5][C:6](=[O:13])[C:7]2[S:12][CH2:11][CH2:10][C:8]=2[N:9]=1)C.Cl.CC(O)=[O:17]>O>[NH:9]1[C:8]2[CH2:10][CH2:11][S:12][C:7]=2[C:6](=[O:13])[NH:5][C:4]1=[O:17]
Reactant: CC(=O)O
Reactant: CCSc1nc2c(c(=O)[nH]1)SCC2
Agent: Cl
Solvent: O
Product: O=c1[nH]c2c(c(=O)[nH]1)SCC2
Temperature: 110 °C
Yield: 82 %

Procedure:
To a suspension of 2-(ethylthio)-6,7-dihydrothieno[3,2-d]pyrimidin-4(3H)-one (2.80 g, 13.06 mmol) in water (2.0 mL) was added 2.0 mL of conc. HCl and 4.0 mL of AcOH. The mixture was heated at 110° C. overnight. The reaction was cooled and the solid that formed collected by filtration washed with water and methanol, and dried to afford a white solid, 6,7-dihydrothieno[3,2-d]pyrimidine-2,4(1H,3H)-dione, (1.80 g, 82%). Without further purification, the crude product was used directly to the next step.