Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][O:38][C:37]([CH3:42])([CH3:41])[CH2:36]1>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][O:38][C:37]([CH3:41])([CH3:42])[CH2:36]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC1(C)CC(CCCBr)CCO1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCOC(C)(C)C3)c2n1
Temperature: 60 °C
Yield: 24.1 %

Procedure:
A mixture of N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate (149 mg, 0.425 mmol) and potassium carbonate (294 mg, 2.126 mmol) in DMF (2 ml) was stirred and heated at 60° C. under nitrogen for one hour. 4-(3-Bromopropyl)-2,2-dimethyltetrahydro-2H-pyran (125 mg, 0.532 mmol) in dry DMF (1 ml) was added and the mixture heated at 60° C. under nitrogen for a further 2.5 hours. The reaction mixture was cooled to room temperature, quenched into water (10 ml) and extracted with DCM:EtOAc (1:1, 2×20 ml). The organic extracts were combined, dried by passage through a hydrophobic frit and concentrated under vacuum. The residue was purified by mass directed autopreparation. Product containing fractions were combined and evaporated to give the title compound (40 mg).
Reaction SMILES: [C:1]1([C:7]2[N:12]3[CH:13]=[N:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[NH:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[S:20]>O1CCCC1.[H-].[Na+]>[C:1]1([C:7]2[N:12]3[C:11]4[N:10]([C:19](=[S:20])[NH:18][C:16](=[O:17])[C:15]=4[N:14]=[CH:13]3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1ncn2c1NCC=C2c1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(=S)n2c3c1ncn3C(c1ccccc1)=CC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 1.0 g of 1,2-dihydro-4-phenylimidazo[1,5-a]pyrimidine-8-carboxamide (prepared as described in Example 29) in 30 ml of dry tetrahydrofuran cooled to -78° C. in a dry ice acetone bath was added in one portion 360 mg of sodium hydride (60% dispersion in mineral oil). The reaction mixture was stirred at -78° C. for 30 minutes then 817 mg of 1,1'-thiocarbonyldiimidazole was added in one portion and the mixture was stirred at -78° C. for 3 hours then allowed to warm slowly to room temperature and was stirred at room temperature for 36 hours. The reaction mixture was quenched with water and neutralized with 5% hydrochloric acid. The aqueous solution was extracted with chloroform. The organic layer was separated and evaporated in vacuo to give the product of the example as a yellow solid, mp 316°-317° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].C([O-])=O.[NH4+:23]>>[NH2:23][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: O=C1CCC(N2Cc3c(Cl)cccc3C2=O)C(=O)N1
Reactant: [NH4+]
Agent: O=C[O-]
Product: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Yield: 85 %

Procedure:
A mixture of 3-(4-chloro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-dioxopiperidine (5 g) in ammonium formate (30 ml) was stirred by heating up slowly to reflux and then reacted under ammonia for 6˜8 hours. The reaction mixture concentrated to dryness under reduced pressure. Recrystallization from heated isopropanol gave 3.96 g of target yield. yield: 85%. Purity: 99.17%. mp: 251.6˜253.9° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=[N:7][OH:8])[NH2:6].Cl.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[N:17]1[CH:18]=[CH:19][C:14]([C:13]2[O:8][N:7]=[C:5]([C:4]3[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][CH:9]=3)[N:6]=2)=[CH:15][CH:16]=1
Reactant: NC(=NO)c1cccc(O)c1
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc(-c2noc(-c3ccncc3)n2)c1

Procedure:
3-(5-Pyridin-4-yl-[1,2,4]oxadiazol-3-yl)phenol was prepared using 3-hydroxybenzamidoxime (3 g, 19.7 mM) and isonicotinyl chloride hydrochloride (3.51 g, 19.6 mM) in pyridine (15 mL) using Preparation 62 to provide 3.65 g of a brown precipitate; m.p., 145-146° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]([C:25]([OH:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH2:30](Cl)CCl.CC1C=CN=C(N)C=1C>ClCCl>[C:21]([O:20][C:18]([NH:17][C@H:15]1[CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C@@H:13]([C:25]([O:27][CH3:30])=[O:26])[CH2:14]1)=[O:19])([CH3:23])([CH3:24])[CH3:22]
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Agent: Cc1ccnc(N)c1C
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of cis (+/−)-1-(benzyloxycarbonyl)-5-(tert-butoxy-carbonylamino)piperidine-3-carboxylic acid (1.0 eq), methanol (20 eq.) and EDC (1.3 eq) in dichloromethane at a concentration of 0.25 M at 0° C. was added dimethyl-aminopyridine (0.1 eq). After stirring for 48 hours as the reaction was allowed to warm to rt the volatiles were removed in vacuo. Upon addition of ethyl acetate and washing with H2O (3×), 1N HCl, NaHCO3 (sat.) and brine, the solution was dried over MgSO4, filtered, concentrated and purified by column chromatography (25% ethyl acetate/hexanes) to yield cis (+/−)-1-benzyl 3-methyl 5-(tert-butoxycarbonylamino)-piperidine-1,3-dicarboxylate. LCMS (m/z): 293.1 (MH-Boc+); LC Rt=4.09 min
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[S:17][CH2:16][CH2:15][CH2:14]2)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[S:17][CH2:16][CH2:15][CH2:14]2
Reactant: CC(C)(C)OC(=O)Nc1cccc2c1SCCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc2c1SCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
10 g (37.7 mmol) of the compound obtained in Step 1 above in 50 ml of dichloromethane are mixed with 50 ml of trifluoroacetic acid, and the mixture is stirred for 30 minutes at room temperature and then evaporated to dryness. The residue is taken up in ether and the solid obtained is filtered off and treated with N sodium hydroxide solution. The aqueous phase is extracted with ether and the ethereal phases are combined, dried over magnesium sulphate and concentrated to yield 4.48 g of the desired product (theory: 6.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(C#N)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 16 %

Procedure:
KH (700 mg, 6.1 mmol) was dissolved in THF (15 mL) at −78° C. and to the solution was added dropwise the solution of 4-amino-3-nitro-benzonitrile (500 mg, 3.1 mmol) in THF (10 mL). After the reaction solution was stirred for 30 minutes, to the solution was added dropwisely methanesulfonyl chloride (0.35 mL, 4.6 mmol) and stirred for 3 hours. The reaction solution was quenched with water and the resulting solution was diluted with ethylacetate. The organic phase was washed with water and brine, dried over anhydride MgSO4 and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane/ethyl acetate=5/1) to yield the nitrile (120 mg, 16%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C)C=O.[O:28]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[OH:1][C:2]1[C:3]([C:8]([NH:39][C:38]2[CH:37]=[CH:36][C:35]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:41][CH:40]=2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1O
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1ncccc1O
Reaction time: 8 h
Yield: 40.5 %

Procedure:
3-Hydroxypicolinic acid (1.39 g, 10.0 mmol) and 1.95 g (12.0 mmol) of carbonyldiimidazole were mixed into anhydrous N,N-dimethylformamide (hereinafter referred to as “DMF”) to prepare a suspension (30 ml). An anhydrous DMF solution (25 ml) of 1.85 g (10.0 mmol) of 4-phenoxyaniline was added dropwise to this suspension, and the reaction was allowed to proceed at room temperature overnight. Water (50 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the dried organic layer was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 1.24 g (yield 41%) of the title compound.
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:21]3[CH2:20][CH2:19][CH2:18][C:17]4([CH2:25][CH2:24][CH2:23][CH2:22]4)[C:16]=3[N:15]=[C:14]([NH2:26])[N:13]=2)(=O)=O)=CC=1.[ClH:27]>C(Cl)Cl.O1CCOCC1>[Cl:27][C:12]1[C:21]2[CH2:20][CH2:19][CH2:18][C:17]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:16]=2[N:15]=[C:14]([NH2:26])[N:13]=1
Reactant: Cl
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC32CCCC2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1nc(Cl)c2c(n1)C1(CCCC1)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 1D (300 mg, 0.803 mmol) in CH2Cl2 (10 mL) was added HCl in dioxane (0.6 mL, 4M), and the mixture stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure, and the resulting residue was chromatographed on silica gel, eluting with 5-20% EtOAc/hexane, to provide the title product. 1H NMR (300 MHz, CDCl3) δ 4.79 (s, 2 H), 2.60 (t, J=6.35 Hz, 2 H), 2.02-2.13 (m, 2 H), 1.82-1.92 (m, 2 H), 1.63-1.79 (m, 6 H), 1.55-1.62 (m, 2 H). MS (DCI+) m/z 357 (M+H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:8]([CH:9]([NH:13][CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C(#N)C>[CH3:14][N:13]([CH:9]([C:8]1[C:3]([C:2]([F:1])([F:15])[F:16])=[N:4][CH:5]=[N:6][CH:7]=1)[CH:10]([CH3:12])[CH3:11])[C:30](=[O:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNC(c1cncnc1C(F)(F)F)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)C(c1cncnc1C(F)(F)F)N(C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
6 g (26 mmol) of 4-trifluoromethyl-5-[1-(N-methylamino)-2-methylpropyl]pyrimidine and 3.6 g (26 mmol) of potassium carbonate were dissolved in 150 ml of acetonitrile, and 4 g (26 mmol) of phenylacetyl chloride was dropwise added, followed by stirring at room temperature for 3 hours. To the reaction solution, 200 ml of water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained crude crystals were washed with n-hexane to obtain 7.7 g (yield: 85%) of N-methyl-N-[2-methyl-1-(4-trifluoromethylpyrimidin-5-yl)propyl]phenylacetamide as colorless transparent crystals (melting point: 106-109° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:17]([F:20])([F:19])[F:18])[O:11][C:12]=2[C:13]([O:15]C)=[O:14])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:17]([F:19])([F:18])[F:20])[O:11][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: COC(=O)c1oc(C(F)(F)F)nc1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1oc(C(F)(F)F)nc1-c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of Methyl 4-(4-fluorophenyl)-2-(trifluoromethyl)oxazole-5-carboxylate (49 mg, 0.17 mmol) in THF (1.5 mL) was added LiOH (21 mg, 0.51 mmol) in water (0.4 mL). After 2 hours, the THF was evaporated, and the aqueous layer was acidified with 1N HCl and then extracted in EtOAc (3×15 mL). The organic fractions were dried over Na2SO4 and concentrated. 1HNMR (400 MHz, MeOD/CDCl3): d 7.99 (m, 2H), 7.03 (t, 2H, J=8.4 Hz). MS (ESI): m/z 274.0 [M−H]− (S-41)
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[C:9]([CH3:31])[C:8]=1[F:32].Cl.Cl.[NH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[C:9]([CH3:31])[C:8]([F:32])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: Cc1c(F)c(N)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1c(F)c(N)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 50 mg of 1-(6-amino-3,5-difluoro-4-methylpyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 40 mg of 3-aminoazetidine dihydrochloride, and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.4 ml of ethanol, the mixture was allowed to cool. The precipitate was collected by filtration, and washed with ethanol and diisopropylether successively to obtain 45 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][N:2]1[C:9]([NH2:10])=[C:8]([NH2:11])[C:6](=[O:7])[N:5]([CH3:12])[C:3]1=[O:4].[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16](O)=O>CO>[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]1[NH:11][C:8]2[C:6](=[O:7])[N:5]([CH3:12])[C:3](=[O:4])[N:2]([CH3:1])[C:9]=2[N:10]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Solvent: CO
Product: Cn1c(=O)c2[nH]c(-c3ccc(Cl)cc3N)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.5 %

Procedure:
1,3-dimethyl-5,6-diaminouracil (0.01 mol) was suspended in 50 ml methanol. 2-amino-4-chlorobenzoic acid (0.01 mol) was added, followed by 0.01 mol of DICD. The reactants were stirred at room temperature for 15 min, then filtered and washed with methanol. The solid was boiled in 40 ml 2.5N NaOH for five min, filtered hot, and the eluate was left to cool for three hours. The material which precipitated on cooling was filtered without washing, redissolved in 40 ml water, and precipitated by neutralization with concentrated HCl. The solid was collected by filtration, washed with H2O, and dried. The product was purified by suspending in 100 ml water, adding NaOH until the compound was dissolved, filtering, precipitating the solid with HCl, filtering, washing with H2O, and drying. The product was identified by chemical ionization mass spectrometry and elemental analysis. Yield 12.5%.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:17][N:18]([CH3:29])[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][N:13]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([N:18]([CH3:29])[CH3:17])=[CH:24][CH:23]=2)(=[O:27])=[O:26])[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CN(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)OC(C)(C)C)c2)cc1

Procedure:
Starting materials: sodium hydride 60% (0.031 g), (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) (0.100 g), 4-dimethylamino-benzenesulfonyl chloride (0.145 g). Reaction conditions: 30° C., 45 min; −30° C., 2.5 hours.
Reaction SMILES: CN1CCOCC1.[O:8]=[C:9]1[CH:14]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[NH:25][CH2:26][C:27](O)=[O:28])[C:16]2=[O:30])[CH2:13][CH2:12][C:11](=[O:31])[NH:10]1.ClC(OCC)=O.[CH:38]1([NH2:41])[CH2:40][CH2:39]1>C1COCC1>[CH:38]1([NH:41][C:27](=[O:28])[CH2:26][NH:25][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:22]=2[C:23](=[O:24])[N:15]([CH:14]2[CH2:13][CH2:12][C:11](=[O:31])[NH:10][C:9]2=[O:8])[C:16]3=[O:30])[CH2:40][CH2:39]1
Reactant: O=C(O)CNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: NC1CC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C1CCC(N2C(=O)c3cccc(NCC(=O)NC4CC4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
N-Methylmorpholine (0.15 g, 1.5 mmol) was added to a stirred suspension of [2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylamino]acetic acid (0.50 g, 1.5 mmol) in 50 mL THF under nitrogen at room temperature. Ethyl chloroformate (0.16 g, 1.5 mmol) was then added. Following 30 minutes stirring at room temperature, cyclopropylamine (0.086 g, 1.5 mmol) was added, and stirring proceeded for 21 hours. The solvent was evaporated in vacuo, and the dark yellow residue was dissolved in ethyl acetate (200 mL) and washed with sat. sodium bicarbonate (2×100 mL), water (100 mL), 1N citric acid (2×100 mL), water (100 mL) and brine (100 mL). The organic phase was dried (MgSO4) and evaporated to provide 0.15 g (27%) of the product as a yellow solid: mp 240-242° C.; 1H NMR (DMSO-d6) δ 0.39-0.45 (m, 2H), 0.59-0.73 (m, 2H), 2.02-2.06 (m, 1H), 2.45-2.70 (m, 3H), 2.96-2.83 (m, 1H), 3.88 (d, J=5.3 Hz, 2H), 5.07 (dd, J=12.5 Hz, J=5.3 Hz, 1H), 6.83-6.92 (m, 2H), 7.07 (d, J=7.0 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 11.11 (s, 1H); 13C NMR (DMSO-d6) δ 5.57, 22.13, 22.26, 30.96, 44.92, 48.59, 109.77, 110.88, 117.42, 132.02, 136.17, 145.80, 167.28, 168.68, 169.46, 170.07, 172.77; Anal. calcd. for C18H18N4O5: C, 58.37; H, 4.90; N, 15.13. Found: C, 58.16; H, 4.64; N, 14.84.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]1[C:12]([NH:19][CH3:20])=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1.C(N(CC)CC)C.ClC([O:31][C:32](Cl)(Cl)Cl)=O>O1CCOCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH2:10][C:11]2[C:12](=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=2)[N:19]([CH3:20])[C:32]1=[O:31]
Reactant: CNc1nc(SC)ncc1CNc1c(C)cccc1C
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1c(C)cccc1C)C2
Temperature: 25 °C
Yield: 46.8 %

Procedure:
A mixture of 195 mg (0.68 mmol) 5-(2,6-dimethylphenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine and 0.19 ml (1.4 mmol) of triethylamine in 10 ml of dioxan was added dropwise to an ice-cooled solution of 0.085 ml (0.7 mmol) of trichloromethyl chloroformate in 10 ml of dioxan. The mixture was then left to warm to room temperature. After a further 10 minutes the mixture was evaporated. To the residue were added 40 ml of dichloromethane and 40 ml of saturated aqueous sodium bicarbonate. The phases were separated and the dichloromethane phase was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 15 ml of pyridine and heated at reflux for 1 hour. The mixture was cooled and evaporated. The residue was partitioned between 20 ml of dichloromethane and 20 ml of 2M hydrochloric acid. The organic phase was washed with 20 ml of water, dried over magnesium sulfate and evaporated to give 100 mg (47%) of 3-(2,6-dimethylphenyl)-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid. [Mass spectrum (ESI) MH+ =315].
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([NH2:4])[CH3:3].O=[C:7]([C:13]([O:15]CC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[OH:15][C:13]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][CH:1]=[C:2]([CH3:3])[N:4]=1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC(N)CN
Solvent: CCO
Product: CCOC(=O)c1ncc(C)nc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
To a solution of propane-1,2-diamine (5.7 mL, 66.4 mmol) in ethanol (100 mL) was added dropwise diethyl ketomalonate (10 mL, 65.6 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr, and then stirred for 1 day with heating under reflux. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a small amount of ethanol, and the solution was passed through silica gel (150 g, eluent, hexane:ethyl acetate=1:1→ethyl acetate). The eluate was concentrated under reduced pressure, and the precipitate was collected by filtration, and washed with diisopropyl ether to give the title compound (2.27 g, 19%) as a pale-orange powder. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→ethyl acetate) to give the title compound (726 mg, 6.1%) as a pale-yellow powder.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([Zn][C:33]#[N:34])#N.Cl[C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]([C:42]([O:44][CH3:45])=[O:43])=[N:40][CH:41]=1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:41]([C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]([C:42]([O:44][CH3:45])=[O:43])=[N:34][CH:33]=1)#[N:40]
Reactant: N#C[Zn]C#N
Reactant: COC(=O)c1ncc(Cl)cc1OC
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(C#N)cc1OC
Temperature: 120 °C
Yield: 86.7 %

Procedure:
In a 350-mL resealable vessel, Pd2dba3 (1.487 g, 1.623 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.444 g, 3.52 mmol), dicyanozinc (3.18 g, 27.1 mmol), and methyl 5-chloro-3-methoxypicolinate (step 1, 5.455 g, 27.1 mmol) were taken up in DMF (80 mL). The reaction mixture was purged with Argon and subsequently heated to 120° C. for 2 h. Upon cooling, the reaction mixture was concentrated under reduced pressure. The residue was filtered through Celite, and the filter cake was rinsed with 1% MeOH/DCM. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (33%-40% EtOAc/hexane) to afford the title compound as a white solid (4.51 g, 23.5 mmol, 87%). MS m/z=193 [M+H]+. Calculated for C9H8N2O3: 192. 1H NMR in CDCl3 δ: 8.51 (d, 1H, J=1.6), 7.55 (d, 1H, J=1.6), 4.00 (s, 3H), 3.97 (s, 3H).
Reaction SMILES: FC(F)(F)S(OC)(=O)=O.[F:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:14][N:15]([CH3:19])[C:16](=S)[CH3:17].[C:24]([O:28][C:29](=[O:42])[NH:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([NH2:40])[CH:38]=2)[CH2:33][CH:32]1[OH:41])([CH3:27])([CH3:26])[CH3:25].N1C=CC=CC=1>C(Cl)Cl>[C:24]([O:28][C:29](=[O:42])[NH:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([N:40]=[C:16]([N:15]([CH2:14][C:13]3[CH:20]=[CH:21][C:22]([F:23])=[C:11]([F:10])[CH:12]=3)[CH3:19])[CH3:17])[CH:38]=2)[CH2:33][CH:32]1[OH:41])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC1c2cc(N)ccc2CC1O
Reactant: CC(=S)N(C)Cc1ccc(F)c(F)c1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=Nc1ccc2c(c1)C(NC(=O)OC(C)(C)C)C(O)C2)N(C)Cc1ccc(F)c(F)c1
Reaction time: 0.5 h
Yield: 298.9 %

Procedure:
Add methyl trifluoromethanesulfonate (0.750 g, 3.49 mmol) to a solution of N-(3,4-difluorobenzyl)-N-methylthioacetamide (0.145 g, 0.736 mmol) in 10 mL of CH2Cl2 at room temperature. Stir the mixture for 30 minutes and remove the solvent under reduced pressure. Then add (6-amino-2-hydroxyindan-1-yl)-carbamic acid t-butyl ester (0.78 g, 2.97 mmol) followed by 5 mL of pyridine. The resulting mixture is stirred for 12 h. After pyridine is evaporated, the residue is purified by column chromatograph (silica gel, 3% MeOH in CH2Cl2) to give 0.98 g of (6-(1-((3,4-difluorobenzyl)-methyl-amino)-ethylideneamino)-2-hydroxyindan-1-yl)-carbamic acid tert-butyl ester as a white solid: MS 446 (MH+).