Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1.Cl.CN.Cl.[CH2:37]([N:39]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>O.CN(C)C=O>[CH3:37][NH:39][C:30]([C:29]1[C:24]([CH2:23][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:22]4[C:13](=[CH:14][C:15]5[O:20][CH2:19][CH2:18][O:17][C:16]=5[CH:21]=4)[O:12][CH2:11]3)[C:2]2=[O:1])=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:31]
Reactant: O=C(O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CNC(=O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.5 %

Procedure:
A 50 mL round-bottom flask was charged with 2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylic acid (0.43 g, 1.0 mmol), methylamine hydrochloride (0.14 g, 2.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.4 mmol), 1-hydroxybenzotriazole (0.20 g, 1.5 mmol), N-methylmorpholine (0.4 mL, 3.6 mmol) and N,N-dimethylformamide (7 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 20 h, and poured into water (200 mL). The solid was collected by filtration, washed with water, dried and purified by column chromatography and eluted with a 0% to 50% gradient of ethyl acetate in dichloromethane to afford N-methyl-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′ (2′H)-yl)methyl]pyridine-3-carboxamide (0.41 g, 92%) as an off-white solid: 1H NMR (300 MHz, CDCl3) 8.43 (d, J=4.8 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.36 (dd, J=7.5, 5.0 Hz, 1H), 7.20-7.07 (m, 2H), 6.95 (t, J=7.5, 1H), 6.81 (d, J=7.8 Hz, 1H), 6.46 (d, J=1.2 Hz, 1H), 6.43 (d, J=1.2 Hz, 1H), 5.16 (ABq, 2H), 4.70 (ABq, 2H), 4.20-4.05 (m, 4H), 2.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.3, 167.6, 154.9, 152.7, 150.1, 144.5, 143.3, 138.1, 136.2, 132.5, 131.6, 129.0, 123.7, 123.1, 122.9, 122.2, 112.4, 109.6, 99.0, 79.7, 64.6, 64.1, 57.7, 43.3, 26.5; MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: CN1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of 1.0 g (5.9 mole) of 4-amino-3-chlorobenzoic acid, 0.8 g (7.0 mole) of 4-amino-1-methyl-piperidine and 4.14 mL (23 mmole) of ethyldiisopropyl amine in 20 mL of dimethylformamide was added a solution of 2.4 g (6.4 mole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate in 5 mL of dimethylformamide. The mixture was stirred at room temperature for 2 hours, then diluted with ice water and saturated sodium carbonate. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) gave 1.41 g of 4-amino-3-chloro-N-(1-methyl-piperidin-4-yl)-benzamide as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:8][CH:9]=1)([O-])=O.[H][H]>[Pd].C(O)(=O)C>[N:12]1([C:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[O:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(c1ccc([N+](=O)[O-])cn1)N1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2CCCCC2)nc1

Procedure:
Crude 5-nitro-2-(piperidin-1-ylcarbonyl)pyridine was reduced by hydrogen under atmospheric pressure in the presence of 10% palladium on carbon (4 g) in acetic acid (500 mL). The catalyst was separated by filtration and the solvent evaporated in vacuum to give crude 6-(piperidin-1-ylcarbonyl)pyridin-3-amine, which was used for the next stage without additional purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.N1C=CC=CC=1.[C:32]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>ClCCl>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[N:6][CH:7]=2)=[O:41])=[CH:43][CH:44]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Reaction time: 0.08 h

Procedure:
To a solution of compound of example 392 (100 mg, 0.295 mmol) in dichloromethane (3 mL), pyridine (70.53 mg, 0.885 mmol) was added and stirred for 5 min. To the reaction mixture, 4-tert-butylbenzoyl chloride (87.27 mg, 0.443 mmol) was added and stirred for about 16 h. After completion of the reaction, the solvent was evaporated and the crude material obtained was triturated with diethyl ether to obtain the title compound, which was filtered and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[N:12]1([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccnc(N2CCNCC2)n1
Yield: 57.9 %

Procedure:
A solution of 2-chloro-4-(trifluoromethyl)pyrimidine (2.0 g, 11 mmol), piperazine (2.8 g, 33 mmol) and triethylamine (3.0 mL, 22 mmol) in DMF (10 mL) was stirred at 100° C. in a sealed tube overnight. After removal of most of the solvent, the residue was purified by column chromatography on silica gel (EtOAc to EtOAc/MeOH/NEt3 9/1/0.5) to give 1.48 g (56%) of desired product. MS calculated for C9H11F3N4: (M+H) 233; found 233.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[CH:7]2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=c1ccc2cccc(F)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cccc2ccc(Cl)nc12
Temperature: 25 °C

Procedure:
8-Fluoroquinolin-2(1H)-one (26 g, 159 mmol) was slurried phosphoryl trichloride (163 mL, 1753 mmol, 11 eq) and heated to 125 for 2 h. The reaction was cooled to rt and poured onto 1.2 L of ice water with vigorous stirring. When mixture had cooled to rt, the orange solid was filtered and washed with water and dried under vacuum overnight to afford 27 g of crude material. The crude material was recrystallized from hexanes by dissolving in ˜700 mL of hexanes at reflux and decanting away from residual tar. The hexane solution was cooled to 0° C. and the precipitate 2-chloro-8-fluoroquinoline was filtered. The mother liquor was concentrated in vacuo and recrystallized from hexanes to obtain a second crop of 2-chloro-8-fluoroquinoline. 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (dd, J=8.6, 1.2 Hz, 1H), 7.62 (br d, 1H), 7.52 (td, J=7.8, 4.7 Hz, 1H), 7.45 (m, 2H).
Reaction SMILES: [Cl-].[CH3:2][NH:3][C:4](=O)[CH3:5].N1C(C)=CC=CC=1C.C(OC([N:22]1[CH2:29][CH2:28][C@:27]2([CH3:32])[C@H:30]([CH3:31])[C@H:23]1[CH2:24][C:25]1[CH:36]=[CH:35][C:34]([C:37]([NH:39][NH2:40])=O)=[CH:33][C:26]=12)=O)(C)(C)C>ClCCl>[CH3:2][N:3]1[C:4]([CH3:5])=[N:40][N:39]=[C:37]1[C:34]1[CH:35]=[CH:36][C:25]2[CH2:24][C@@H:23]3[C@@H:30]([CH3:31])[C@:27]([CH3:32])([C:26]=2[CH:33]=1)[CH2:28][CH2:29][NH:22]3
Reactant: CNC(C)=O
Reactant: C[C@@H]1[C@H]2Cc3ccc(C(=O)NN)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1nnc(-c2ccc3c(c2)[C@]2(C)CCN[C@H](C3)[C@H]2C)n1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Oxalylic chloride (0.12 mL) is added to a solution N-methylacetamide (102 mg) and 2,6-lutidine (0.33 mL) in dichloromethane (5 mL) chilled in an ice bath. After stirring the solution for 15 min, (2R,6R,11S)-8-hydrazinocarbonyl-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (0.50 g) is added and the cooling bath is removed. The resulting solution is stirred at ambient temperature for 1 h and then neutralized with aqueous NaHCO3 solution. The resulting mixture is extracted with dichloromethane, the combined organic extracts are dried (MgSO4), and the solvent is evaporated. The residue is taken up in acetic acid (3 mL) and stirred at 120° C. for 2.5 h. After cooling to room temperature, the mixture is concentrated under reduced pressure and the residue is taken up in trifluoroacetic acid (1 mL) and dichloromethane (5 mL) to cleave off the tert-butoxycarbonyl group. The solution is stirred at room temperature overnight and then concentrated. The residue is dissolved in little methanol/acetonitrile, neutralized with aqueous ammonia, and purified by HPLC on reversed phase (MeCN/H2O/NH4OH) to give the title compound.
Reaction SMILES: N#N.[Br:3][C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][N:5]=1.COC([O:18][CH3:19])OC.[C:20]([O-])([O-])=O.[Na+].[Na+]>C(O)CO>[Br:3][C:4]1[CH:9]=[C:8]([C:10]2([CH3:11])[O:18][CH2:19][CH2:20][O:12]2)[CH:7]=[CH:6][N:5]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccnc(Br)c1
Reactant: COC(OC)OC
Agent: N#N
Agent: [Na+]
Solvent: OCCO
Product: CC1(c2ccnc(Br)c2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-(2-bromo-pyridin-4-yl)-ethanone (1650 mg, 8.25 mmol) in ethylene glycol (8.8 mL) was treated with trimethylorthoformate (1.85 mL, 16.88 mmol) followed by LiBF4 (158 mg, 1.65 mmol). The reaction mixture was heated at 95° C. overnight. Sat. aq. Na2CO3 (20 mL) was added and the mixture was extracted with Et2O (2×30 mL). The org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:1 to 2:1 hept-EA) gave the title compound as a yellow oil. TLC:rf (1:1 hept-EA)=0.57. LC-MS-conditions 02: tR=0.88 min; [M+H]+=244.19.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14]COC)=[CH:12][CH:11]=[CH:10][C:9]=1[O:18]COC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CO>[CH2:1]([C:8]1[C:9]([OH:18])=[CH:10][CH:11]=[CH:12][C:13]=1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1cccc(OCOC)c1Cc1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1cccc(O)c1Cc1ccccc1
Yield: 100.6 %

Procedure:
A solution of 13 (214 mg, 0.74 mmol) in MeOH (6.20 mL) was treated dropwise with 3 M HCl (0.22 mL, 5.92 mmol), then heated to reflux for one hour. Water (10 mL) was added and the solution was extracted with EtOAc (3×15 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), and concentrated to afford 14 as a red amorphous solid (149 mg, 99%). 1H NMR (CDCl3, 400 MHz) δ 7.31 (d, J=6.6 Hz, 4H), 7.25-7.19 (m, 1H), 7.01 (t, J=8.1 Hz, 1H), 6.44 (d, J=8.1 Hz, 2H), 4.82 (s, 2H), 4.09 (s, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([O:10][CH:11]([CH3:14])[CH2:12][CH3:13])=[O:9])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:26](O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[NH2:1][C@H:2]([C:8]([O:10][CH:11]([CH3:14])[CH2:12][CH3:13])=[O:9])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[NH2:1][C@H:2]([C:8]([O:10][CH:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:27][CH3:26])=[O:9])[CH2:3][CH2:4][C:5]([O-:7])=[O:6]
Reactant: CCC(C)OC(=O)[C@H](N)CCC(=O)[O-]
Reactant: CCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC(C)OC(=O)[C@@H](N)CCC(=O)[O-]
Product: CCCCCCCCCC(CC)OC(=O)[C@@H](N)CCC(=O)[O-]

Procedure:
To a solution of 20 g of poly (γ-butyl D-glutamate) (molecular weight 42,000, average degree of polymerization 230) prepared by the NCA method were added 150 ml of n-dodecyl alcohol and 5 g of p-toluenesulfonic acid. The mixture was allowed to react at 60° C. for 20 hours. The reaction mixture was treated in the same way as in Reference Example 1 to obtain a γ-butyl L-glutamate-γ-dodecyl L-glutamate copolymer. Ratio of the butyl ester to the dodecyl ester in the copolymer was 40:60 by NMR measurement.
Reaction SMILES: [Na+].[I-].C[Si](Cl)(C)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)O)=[CH:11][CH:10]=1.O>CC#N>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1
Reactant: OC(c1ccc(F)cc1)c1cccs1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Fc1ccc(Cc2cccs2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a suspension of NaI (8 g, 53 mmol) in CH3CN (100 mL) was added TMSCl (6.8 mL, 54 mmol). The resulting mixture was cooled to 0° C. and treated with (4-fluorophenyl)-2-thienylmethan-1-ol, allowed to warm to room temperature, stirred overnight, then cooled to 0° C. and treated with water. The resulting mixture was extracted with EtOAc. The organic layer was washed with a saturated Na2S2O3 solution, water and a saturated NaCl solution, then concentrated under reduced pressure. The crude product was purified by flash chromatography (hex) to give 2-(4-fluorobenzyl)thiophene (1.89 g, 40% overall yield) as a pink oil: TLC (hex) Rf 0.69; 1H NMR (CDCl3) δ 4.14 (s, 2H), 6.80-6.82 (m, 1H), 6.93-7.04 (s, 3H), 7.16-7.28 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([O:11][CH3:12])[N:5]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:3]=1>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[C:6]([O:11][CH3:12])[C:7]=1[NH2:8]
Reactant: COc1nc(N2CCOCC2)cc(Cl)c1[N+](=O)[O-]
Agent: Cl
Product: COc1nc(N2CCOCC2)cc(Cl)c1N
Temperature: 75 °C
Yield: 61.6 %

Procedure:
To a solution of 4-(4-chloro-6-methoxy-5-nitropyridin-2-yl)-morpholine (0.82 g) in concentrated hydrochloric acid (50 mL) was added a solution of stannous dichloride (3.38 g) in concentrated hydrochloric acid (80 mL). The reaction mixture was heated to 75° C. for 1 hour and then poured on to chrushed ice (400 g) and extracted with ethyl acetate (2×100 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo, to furnish 0.45 g (61% yield) of the title compound as an off-white solid. LC-MS (m/z) 244 (M+); tR=1.48, (UV, ELSD) 89%, 94%. 1H NMR (500 MHz, CDCl3): 3.30 (m, 4H), 3.65 (br s, 2H), 3.85 (m, 4H), 3.97 (s, 3H), 6.20 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][C:14]4([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:13][C:14]4([CH2:20][CH2:19][N:18]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:17][CH2:16]4)[CH2:15]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CC4(CCNCC4)C3)cc2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a solution of 2-chloro-6-(2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (71 mg, 0.18 mmol) in anhydrous DCM (3 mL) was added triethylamine (160 μL, 1.46 mmol) and a solution of methanesulfonyl chloride (17 μL, 0.22 mmol) in anhydrous DCM (0.5 mL). The resulting mixture was stirred at RT for 18 h, then diluted with DCM and brine. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow oil (55 mg, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:20][CH2:21]C2C=CC=C(OC)C=2)[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH:5]=O.[CH3:30]/[C:31](/[NH2:35])=[CH:32]\[C:33]#[N:34].[CH2:36]([CH:39]1[CH2:44][C:43](=O)[CH2:42][C:41](=[O:46])[CH2:40]1)[CH2:37][CH3:38]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:42]3[C:41](=[O:46])[CH2:40][CH:39]([CH2:36][CH2:37][CH3:38])[CH2:44][C:43]=3[NH:35][C:31]([CH3:30])=[C:32]2[C:33]#[N:34])[CH:7]=[C:8]([O:20][CH2:21][C:3]2[CH:4]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[CH:2]=2)[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: CCCC1CC(=O)CC(=O)C1
Reactant: COc1cccc(COc2cc(C=O)cc(Br)c2OCc2cccc(OC)c2)c1
Reactant: C/C(N)=C\C#N
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(OC)c2)c(OCc2cccc(OC)c2)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of 3-bromo-4,5-bis-(3-methoxy-benzyloxy)-benzaldehyde (143 mg), 3-aminocrotonitrile (28 mg), 5-propylcyclohexane-1,3-dione (52 mg) in ethanol (10 ml) was stirred at 80° C. for 17 h. The mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/1→2/8 (v/v) as eluent.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([Cl:17])[N:9]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C>CS(C)=O>[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:10]([Cl:17])[N:9]=1.[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:14]2)=[C:10]([Cl:17])[N:9]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Clc1nc(Cl)c2c(ncn2Cc2ccccc2)n1
Product: Clc1nc(Cl)c2ncn(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 4.56 potassium carbonate and 5.67 g of 2,6-dichloropurine in 40 ml of dimethylsulfoxide was added, 5.64 g of benzylbromide. The mixture was stirred for 45 minutes under nitrogen at room temperature and was then poured onto crushed ice. The pH of the mixture was adjusted to 5 with acetic acid and extracted with methylene chloride (2×400 ml). The combined extracts were washed with water (6×400 ml), and brine (1×400 ml), dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using chloroform-methanol (9:1-V:V) as the eluent to give 3.59 g of 2,6-dichloro-9-benzylpurine, m.p. 152°-152.5° C. and 1.32 g of 2,6-dichloro-7-benzylpurine, m.p. 151°-151.5° C.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[N:5]([CH2:11][CH3:12])[C:4]1=[O:13])[CH3:2].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Sn](Cl)(Cl)(Cl)Cl.ClC1C=CC=CC=1>CCOC(C)=O>[C:14]([C:7]1[C:6](=[O:10])[N:5]([CH2:11][CH3:12])[C:4](=[O:13])[N:3]([CH2:1][CH3:2])[C:8]=1[CH3:9])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCn1c(C)cc(=O)n(CC)c1=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CCn1c(C)c(C(=O)c2ccccc2)c(=O)n(CC)c1=O
Temperature: 25 °C

Procedure:
1,3-Diethyl-6-methylpyrimidine-2,4(1H,3H)-dione (step 1)(680 mg, 3.73 mmol), benzoyl chloride (1.299 mL, 11.20 mmol) and tin(IV) chloride (1.314 mL, 11.20 mmol) were combined in chlorobenzene (30 mL, 295 mmol) and the mixture heated at reflux for 16 h. The reaction mixture was cooled to RT and diluted with EtOAc. The mixture was washed with 2M NaOH(aq) until basic. The organic phase was washed with brine, dried over sodium sulphate and evaporated under vacuum. The residue was dissolved in DCM and evaporated onto silica. The silica was deposited onto a 10 g silica cartridge and the system eluted with 10% EtOAc/hexane, 20% EtOAc/hexane, 40% EtOAc/hexane and 50% EtOAc/hexane. Product elutes at 40% EtOAc/hexane. Fractions were concentrated under vacuum to yield the title compound as an off white solid;
Reaction SMILES: [S:1]1[C:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]=2[NH:3][C:2]1=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH:23](I)[CH3:24].[OH-].[K+]>C(O)C>[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][N:3]1[C:4]2[CH:13]=[CH:12][C:11]3[C:6]([C:5]=2[S:1][C:2]1=[O:14])=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: O=c1[nH]c2ccc3ccccc3c2s1
Reactant: COCCOCCOC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCCOCCOCCn1c(=O)sc2c3ccccc3ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.0 g of naphtho[2,1-d]thiazoline-2-on, 3.0 g of 2-methoxyethoxyethoxy-1-iodoethane (synthesized from methoxyethoxyethoxyethyl p-toluenesulfonate and sodium iodide), 0.6 g of potassium hydroxide and 20 ml of ethanol were fed into a 50 ml short-neck flask provided with a reflux condenser, and heated under reflux and under stirring for 4 hours. After cooling to room temperature followed by extraction with 300 ml of ethyl acetate and 150 ml of water, the thus-obtained ethyl acetate layer was dried over sodium sulfate, and ethyl acetate was distilled off under reduced pressure. The obtained compound was purified by column chromatography (hexane:ethyl acetate=1:1) to obtain the intended compound.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[CH3:7][C:8]([C:13]1[S:17][C:16]([NH:18][C:19](=[O:25])[CH:20]([NH2:24])[CH2:21][CH2:22][CH3:23])=[N:15][N:14]=1)([CH3:12])[CH2:9][CH2:10][CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCl.CN(C=O)C>[CH3:12][C:8]([C:13]1[S:17][C:16]([NH:18][C:19](=[O:25])[CH:20]([NH:24][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[CH2:21][CH2:22][CH3:23])=[N:15][N:14]=1)([CH3:7])[CH2:9][CH2:10][CH3:11]
Reactant: CCC(=O)CC
Reactant: CCCC(N)C(=O)Nc1nnc(C(C)(C)CCC)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCC(NC(CC)CC)C(=O)Nc1nnc(C(C)(C)CCC)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of pentan-3-one (0.3 mmol), 2-Amino-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide (0.3 mmol), sodium triacetoxy borohydride (0.3 mmol) and acetic acid (0.3 mmol) in 1.0 mL of anhydrous dichloromethane and 1 ml DMF was stirred at room temperature (rt) overnight. The reaction was not complete. The mixture was treated with NaBH3CN (40 mg) and heated at 45° C. for 4 hr. All starting material was consumed. The crude solution was diluted with dilute NaOH and extracted with methylene chloride. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified through Shimadzu HPLC to give 2-(1-Ethyl-propylamino)-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide. LC-MS (retention time, M+1): 1.70 min, 355.3 [M+1]