Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH:14]1([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=3)[CH:20]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(#N)C>[CH:14]1([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([NH:26][C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([O:9][CH2:8][C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[CH:32][CH:33]=3)[CH:20]=2)[CH2:16][CH2:15]1
Reactant: Cc1cccnc1CO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ncccc2C)cc1
Temperature: 80 °C
Yield: 102.2 %

Procedure:
To (3-methylpyridine-2-yl)methanol (157 mg, 1.272 mmol) in DCM (5 mL) was added thionyl chloride (200 μl) and the mixture stirred and heated at reflux for 4 h. The mixture was evaporated to dryness. To the residue was added N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (197 mg, 0.636 mmol) and potassium carbonate (176 mg, 1.27 mmol) in acetonitrile (5 mL) and the resulting mixture heated at 80° C. for 16 h. The reaction mixture was cooled and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was concentrated under reduced pressure. Precipitation with DCM in diethyl ether gave the title compound as a solid (270 mg); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H), 2.40 (s, 3H), 2.86 (m, 1H), 5.30 (s, 2H), 7.17 (d, 2H), 7.33 (m, 2H), 7.65 (m, 2H), 7.82 (s, 1H), 7.97 (d, 2H), 8.39 (m, 2H), 9.81 (s, 1H); Mass Spectrum: M+H+ 416.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[C:23]([C:30]4[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][CH:27]([F:28])[C:25]1[CH:24]=[C:23]([C:30]2[CH:31]=[N:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.3 %

Procedure:
To a cooled and stirred solution of 3′-[4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.56 g) in dichloromethane (7 ml) was added TFA (7 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.41 g, 81%). MS (ISP) 507.2 [(M+H)+]; mp 222° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:14]1([CH:20]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:21][CH2:22][NH:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:33]([O:32][C:30]([N:27]1[CH2:26][CH2:25][CH:24]([N:23]([CH2:22][CH2:21][CH:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)=[O:11])[CH2:29][CH2:28]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(NCCC(c2ccccc2)c2ccccc2)CC1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2cccc(C(F)(F)F)c2)CC1
Reaction time: 0.75 h
Yield: 87.4 %

Procedure:
246 mg (1.32 mmol) of 3-(trifluoromethyl)phenyl isocyanate is added to a solution of tert-butyl 4-[(3,3-diphenylpropyl)amino]-1-piperidine carboxylate (470 mg, 1.2 mmol) in 5 ml of dichloromethane. The solution is agitated for 45 minutes, and the aminomethyl resin (180 mg, 0.36 mmol) is added and the reaction medium is again placed on an orbital shaker for 45 minutes. The resin is filtered and washed with dichloromethane. The filtrate is concentrated in vacuo in order to produce 610 mg (yield=87%) of a white foam.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:21]=[C:20]([C:22]([OH:24])=O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:8][C:7]=1[O:25][CH3:26])[CH2:2][CH2:3][CH3:4]>S(Cl)(Cl)=O>[CH2:20]([CH:19]([CH2:18][CH2:17][CH2:16][CH3:15])[CH2:14][NH:13][C:22]([C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:7]([O:25][CH3:26])[CH:8]=2)[CH:21]=1)=[O:24])[CH3:21]
Reactant: CCCCOc1ccc(-c2cc(C(=O)O)c3ccccc3n2)cc1OC
Solvent: O=S(Cl)Cl
Product: CCCCOc1ccc(-c2cc(C(=O)NCC(CC)CCCC)c3ccccc3n2)cc1OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
10.5 g of 2-(4'-butyoxy-3'-methoxyphenyl)quinoline-4-carboxylic acid (prepared as described in Example 7) were dissolved in 50 g of thionyl chloride, and the solution was refluxed for half an hour. The excess thionyl chloride was distilled off under reduced pressure, and the residue was introduced into 50 g of 2-ethylhexylamine with ice-water cooling. The mixture was stirred at 25° C. for 1 hour and at 80° C. for a further half hour. After cooling, 200 ml of methanol were added to dilute the mixture, and the precipitated product was washed with methanol and water and dried at 60° C. in a drying cabinet. 6.5 g were obtained of N-(2'-ethylhexyl)-2-(4'-butoxy-3'-methoxyphenyl)quinoline-4-carboxamide. The colorless crystals melt at 118° C. and have a λmax in toluene at 352 nm. In 2% strength methanolic hydrochloric acid the λmax is 403 nm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([OH:11])=[O:10].[OH-].[Na+:13]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([O-:11])=[O:10].[Na+:13]
Reactant: Cc1ccc(Br)c(S(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(Br)c(S(=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
49.6 g of 2-bromo-5-methylbenzenesulfinic acid are dissolved in 400 ml of methanol and treated with an equimolar amount of NaOH in 50 ml of water. The mixture is stirred at RT for 3 hours, the solution is filtered off and subsequently the solvents are removed in vacuo. Finally, water residues are removed azeotropically with 50 ml of toluene. The solid residue is dried over P4O10 in vacuo and 54.0 g of product are obtained, mp 288-290° C. (with decomposition).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]1[C:15]1[NH:16][CH:17]=[C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([C:36]4[N:37]=[C:38]([C@@H:41]5[CH2:45][C@H:44]([CH3:46])[CH2:43][N:42]5C(OC(C)(C)C)=O)[NH:39][CH:40]=4)=[CH:32][CH:31]=2)[CH:24]=[CH:23]3)[N:19]=1)=O)(C)(C)C>O1CCOCC1.CO>[CH3:46][C@@H:44]1[CH2:43][NH:42][C@H:41]([C:38]2[NH:39][CH:40]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:25]4[CH:24]=[CH:23][C:22]5[C:27](=[CH:28][CH:29]=[C:20]([C:18]6[N:19]=[C:15]([C@@H:10]7[CH2:11][C@H:12]([CH3:14])[CH2:13][NH:9]7)[NH:16][CH:17]=6)[CH:21]=5)[CH:26]=4)=[CH:31][CH:32]=3)[N:37]=2)[CH2:45]1
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7C[C@H](C)CN7C(=O)OC(C)(C)C)n6)ccc5c4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H]1CN[C@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7C[C@H](C)CN7)n6)ccc5c4)cc3)c[nH]2)C1
Reaction time: 2 h

Procedure:
A solution of 4N HCl in dioxane (15 mL) was added to tert-butyl(2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinecarboxylate (200 mg. 0.285 mmol) in MeOH (5 mL) and stirred at ambient conditions for 2 hours, concentrated, and dried under vacuum. Tetra HCl salt (assume theoretical: 185 mg). LC-MS retention time 2.64 min; Calcd. for C32H35N6: 503.29 m/z Found 503.20 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: C(N(CC)CC)C.[CH2:8](Cl)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)/C=C\C(O)=O>O1CCCC1.CC(C)=O>[CH2:8]([NH:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCC=Cc1ccccc1
Reactant: NCc1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C(=Cc1ccccc1)CNCc1ccccc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
113 ml (818 mmol) of triethylamine were added to 96.4 g (600 mmol) of cinnamyl chloride in 800 ml of tetrahydrofuran, the mixture was heated to 60° C., and then 65.4 ml (600 mmol) of benzylamine were added dropwise. The mixture was refluxed for 3 h and then stirred at room temperature for 15 h. After concentration under water pump vacuum, the contents of the flask were partitioned between methyl t-butyl ether and water (pH=10). The organic phase was washed twice with water, dried with sodium sulfate and concentrated. The crude product (109 g) composed of mono- and bisadduct was dissolved in 400 ml of acetone, a solution of 48 g (413 mmol) of maleic acid in 250 ml of acetone was added while stirring and, after cooling, the precipitated solid was filtered off with suction. After washing with acetone, 60.0 g (30%) of N-cinnamylbenzylamine were isolated as maleate, melting point 169°-170° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11](C(O)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)N1CCN(c2ccc(O)cc2)c2ccccc21
Reactant: ClCc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(COc2ccc(N3CCNc4ccccc43)cc2)nc1
Temperature: 100 °C

Procedure:
0.3 g of the tert-Butyl ester of 4-(4-hydroxyphenyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is placed in 4.6 ml of dimethylformamide under nitrogen. 0.167 g of 2-(chloromethyl)pyrimidine and 0.508 g of potassium carbonate are added. The reaction medium is heated at 100° C. for 4 h. 0.254 g of potassium carbonate is added and heating is maintained for 1 h 30. After hydrolysis, the reaction medium is extracted with ethyl acetate until the aqueous phase has been completely extracted. The organic phases are combined, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of methanol in dichloromethane varying from 0% to 9/1. 0.095 g of 1-[4-(pyrimidin-2-ylmethoxy)phenyl]-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:26][O:27][CH3:28])=[C:10](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+].Cl>CCO.[Cl-].[Na+].O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:26][O:27][CH3:28])=[C:10](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(COC)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCn1ncc2c(-c3cncc(C)c3)c(/C=C/C(=O)O)c(COC)nc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a stirred solution of ethyl (2E)-3-[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]acrylate (30 mg) in EtOH (2 ml) was added 1N aqueous NaOH (0.16 ml) and the mixture was stirred at 40° C. for 1 hour. After cooling, the reaction mixture was acidified to pH3-4 by adding 1N HCl (0.16 ml). The mixture was diluted with brine and extracted with CHCl3. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography eluting with a mixture of MeOH and CHCl3 (1:10). The residue was recrystallized from EtOAc-n-hexane to give (2E)-3-[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]acrylic acid (15 mg) as a colorless crystal.
Reaction SMILES: C([Mg]Br)C.[CH2:5]([OH:9])[CH2:6][C:7]#[CH:8].Cl[Si:11]([CH3:14])([CH3:13])[CH3:12].S(=O)(=O)(O)O>O1CCCC1>[CH3:12][Si:11]([CH3:14])([CH3:13])[C:8]#[C:7][CH2:6][CH2:5][OH:9]
Reactant: C#CCCO
Reactant: C[Si](C)(C)Cl
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A solution of 2 mol of ethyl magnesium bromide (2.0 molar solution in tetrahydrofuran) is cooled in an ice bath and a solution of 50.5 g of 3-butyn-1-ol (0.72 mol) in 50 ml of tetrahydrofuran is slowly added. After addition is complete, the mixture was allowed to warm to room temperature and was stirred overnight. The mixture was then cooled in an ice bath and 254 ml (2 mol) of chlorotrimethylsilane was slowly added. This mixture was heated under reflux for two hours and then cooled to 20° C. and 800 ml of 1.4 M aqueous sulfuric acid were added. The mixture was extracted with diethyl ether and the ether solution was dried and concentrated under vacuum. The residue was distilled to yield 72.8 g of 4-trimethylsilyl-3-butyne-1-ol, bp 43° -48° C. at 1 mm Hg.
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[O:9][C:5]=2[C:4](=[O:14])[NH:3][CH:2]=1.[CH3:15][O:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][CH3:26])=[O:24])[C@H:18]1[CH2:27][C:28](=[O:31])[CH2:29]Br>>[O:14]=[C:4]1[N:3]([CH2:29][C:28](=[O:31])[CH2:27][C@H:18]2[C@H:17]([O:16][CH3:15])[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([O:25][CH3:26])=[O:24])[CH:2]=[N:1][C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[O:9][C:5]1=2
Reactant: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: O=c1[nH]cnc2c1oc1ccccc12
Product: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2c(oc3ccccc32)c1=O

Procedure:
According to the method of Example 1, 1.22 g (0.0066 mole) of benzofuro[3,2-d]pyrimidin-4(3H)-one [S. S. Sangapure and Y. S. Agasimundin, Indian J. Chem., 14B, 688-691 (1976)] and 0.0066 moles of methyl trans-3-methoxy-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate were combined to give the title compound: yield 0.627 g (23%); 1H-nmr (CDCl3) delta 1.2-2.1 ppm (multiplet, 4H, CH3OCHCH2CH2CH2N), 2.7-3.2 (multiplet, 4H, NCH2), 2.9 (doublet, 2H, COCH2CH), 3.3 (singlet, 3H, CHOCH3), 3.7 (singlet, 3H, CO2CH3), 4.0 (broad doublet, 1H CHOCH3), 4.9 (broad triplet, 1H, CH2CHNCO), 5.2 (singlet, 2H, NCH2CO), 7.3-7.7 (multiplet, 3H, aromatic H), 8.0 (doublet, 1H, aromatic H), 8.2 (singlet, 1H, N=CH--N).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[C:39]([NH:41][NH2:42])=[O:40])(=[O:13])=[O:12].[CH:43](=O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(O)C>[CH:43](=[N:42][NH:41][C:39]([C@@H:15]1[CH2:16][C@@H:17]([S:19][C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:18][N:14]1[S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12])=[O:40])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NNC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: O=C(NN=Cc1ccccc1)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 80 °C
Yield: 79.9 %

Procedure:
(step 10) To a suspension of 3.0 g (5.05 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid hydrazide in ethanol were added 0.56 ml (5.6 mmol, 1.1 eq) benzaldehyde at RT, and the reaction mixture was heated to 80° C. for 3 h. The solvent was evaporated and the residue was purified by flash chromatography on silica gel with ethyl acetate:hexane 1:1 as eluent yielding 2.75 g (80%) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid benzylidene-hydrazide as white foam, MS: 682 (MH+).
Reaction SMILES: [CH:1]1[NH:2][C:3]2[N:9]=[C:8]([NH2:10])[N:7]=[C:6](Cl)[C:4]=2[N:5]=1.C(N(CC)CC)C.CC1C=C(C)C(S)=CC=1.[OH2:28]>CO>[NH:7]1[C:6](=[O:28])[C:4]2[NH:5][CH:1]=[N:2][C:3]=2[N:9]=[C:8]1[NH2:10]
Reactant: O
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Agent: Cc1ccc(S)c(C)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nc2nc[nH]c2c(=O)[nH]1

Procedure:
6-Chloroguanine derivative prepared in Preparation 6 (4.86 g) was dissolved in 85 ml of methanol and 1.4 g of triethylamine and 2.9 g of 4-methylthiocresol were added. The reaction mixture was reacted under reflux condition for 24 hours. The reaction was stopped by adding 20 ml of water, and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichloromethane and purified by silica gel column to give a compound wherein 6-position of guanine was substituted by 4-methylphenylthio group.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([N:8]1[CH2:46][CH2:45][CH2:44][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:28]([NH:30][CH2:31][C:32]([O:34][C:35]1[CH:43]=[CH:42][C:38]([N+:39]([O-:41])=[O:40])=[CH:37][CH:36]=1)=[O:33])=[O:29])[CH2:18][CH:19](OC(C)(C)C)[C:20](=[O:22])[OH:21])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57]>C(Cl)Cl>[NH2:1][C@H:2]([C:6]([N:8]1[CH2:46][CH2:45][CH2:44][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:28]([NH:30][CH2:31][C:32]([O:34][C:35]1[CH:36]=[CH:37][C:38]([N+:39]([O-:41])=[O:40])=[CH:42][CH:43]=1)=[O:33])=[O:29])[CH2:18][CH2:19][C:20](=[O:21])[OH:22])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5].[F:54][C:55]([C:56]([OH:58])=[O:57])([F:60])[F:59]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(OC(C)(C)C)C(=O)O)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CCC(=O)O)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of XX (1.1 g, 1.50 mmol) in 9 ml of 30% trifluoroacetic acid in methylene chloride was allowed to stand for 30 min. at room temperature. The reaction mixture was treated in the same manner as described for the preparation of XI in part (j). The resulting solid was recrystallized from chloroform-petroleum ether; yield 0.923 g (90%), m.p. 130-133° C., Rf1 0.06, Rf2 0.12, Rf3 0.21. Calcd. for C27H35N6O12F3.1/2H2O: C, 46.22; H, 5.17; N, 11.98%. Found: C, 46.06; H, 5.16; N, 11.82%. Amino acid analysis: Glu, 0.98; Pro, 0.90; Gly, 2.10; Val, 1.00.
Reaction SMILES: Cl.[CH2:2]1[C:5]2([CH2:8][CH:7]([NH:9][C:10]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:18][CH:17]=4)=[C:14]([NH2:29])[N:13]=[CH:12][N:11]=3)[CH2:6]2)[CH2:4][NH:3]1.CCN(C(C)C)C(C)C.[C:39](O)(=[O:42])[C:40]#[CH:41].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(Cl)Cl>[NH2:29][C:14]1[N:13]=[CH:12][N:11]=[C:10]([NH:9][CH:7]2[CH2:8][C:5]3([CH2:4][N:3]([C:39](=[O:42])[C:40]#[CH:41])[CH2:2]3)[CH2:6]2)[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][CH:17]=1
Reactant: Nc1ncnc(NC2CC3(CNC3)C2)c1-c1ccc(Oc2ccccc2)cc1
Reactant: C#CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)N1CC2(CC(Nc3ncnc(N)c3-c3ccc(Oc4ccccc4)cc3)C2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
In a microwave vial containing N-(2-Aza-spiro[3.3]hept-6-yl)-5-(4-phenoxy-phenyl)-pyrimidine-4,6-diamine hydrochloride (80.00 mg; 0.20 mmol; 1.00 eq.) in DCM (1.00 ml) was added DIPEA (0.16 ml; 0.98 mmol; 5.00 eq.) and propiolic acid (24.20 μl; 0.39 mmol; 2.00 eq.) followed by 2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (0.12 ml; 0.29 mmol; 1.50 eq.). The reaction was stirred at rt for 1 h before it was concentrated and purified by preparative HPLC (0.1% TFA-H2O/ACN). Fractions containing the desired product were combined and lyophilized overnight to afford 1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-yn-1-one as a white solid (27.8 mg, 26.1%). HPLC purity: 99%. MS: m/z=426 [M+H]+. 1H NMR (CD3OD) δ 8.25 (s, 1H), 7.18-7.49 (m, 9H), 4.32 (d, 1H), 4.09 (d, 2H), 3.89 (d, 1H), 2.60 (m, 2H), 2.29 (m, 2H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[ClH:15].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([Cl:1])=[O:10])[CH2:5][CH2:4]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 111.1 %

Procedure:
To a suspension of 1-methyl-piperidine-4-carboxylic acid hydrochloride (11.36 mmol, 2.04 g) and N,N-dimethylformamide (0.129 mmol, 0.01 ml, 9.40 mg) in dichloromethane (10 ml) at 0° C. was added oxalyl chloride (14.76 mmol, 1.40 ml) drop wise. The cooling bath was removed and the reaction mixture stirred at room temperature for 20 hours. Then the reaction mixture was concentrated in vacuo to give 1-methylpiperidine-4-carbonyl chloride hydrochloride (2.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:17][CH2:18][C:19](O)=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:10]([O:17][CH2:18][C:19]1[NH:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([OH:9])[C:2]=2[N:1]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(O)c1N
Reactant: O=C(O)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Oc1cccc2[nH]c(COCc3ccccc3)nc12
Temperature: 140 °C
Yield: 67 %

Procedure:
A mixture of the 2,3-diaminophenol (5 g, 40.3 mmol, 1 eq) and benzyloxyacetic acid (5.6 g, 48.3 mmol, 1.2 eq) in 40 ml of a 10% aqueous solution of sodium bicarbonate was stirred and refluxed at 140° C. for one hour. The mixture was allowed to cool down to room temperature. Ethyl acetate was poured into the mixture. The organic fraction was extracted with ethyl acetate, washed with water, and then dried over sodium sulfate. The solvents were removed in vacuo. The crude product was further purified by flash chromatography to yield 6.87 grams (67% yield) of the desired title product.