Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N[C@H:12]([C:17]([NH2:19])=[O:18])[C@H:13]([CH2:15]O)O)=O)C1C=CC=CC=1.[Cl:20][CH2:21][C:22]([N:24]=[C:25]=[O:26])=[O:23].CN(C=[O:31])C>>[Cl:20][CH2:21][C:22]([NH:24][C:25]([O:31][NH:19][C:17](=[O:18])[CH2:12][CH2:13][CH3:15])=[O:26])=[O:23]
Reactant: NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](O)CO
Reactant: CN(C)C=O
Reactant: O=C=NC(=O)CCl
Product: CCCC(=O)NOC(=O)NC(=O)CCl
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 0.268 g (1 mM) of Nα-benzyloxycarbonyl-4-hydroxy-L-allothreoninamide in 5 mL DMF was cooled to -10° C. and 0.12 g (1 mM) chloroacetylisocyanate was added and the reaction was stirred at -10° C. for 1 hr to give (2S,3S)-2-benzyloxy-carboxamido-3-hydroxy-4-(N-chloroacetylcarbamoyloxy-butanamide. To the above reaction mixture, 0.148 g (1.25 mM) methanesulfonylchloride was added at -15° to -10° C. and 0.26 mL triethylamine was added subsequently. The reaction mixture was stirred at -15° to -10° C. for 40 min. After the reaction, ethylacetate (20 mL) was added. The resulting mixture was washed with 5% aqueous NaH2PO4, brine and the organic layer was dried over Na2SO4. Solvent was removed at the reduced pressure and the crude product was purified by column chromatograph (SiO2, EtOAc:Hexane-8:2) to give (2S, 3S)-2-benzyloxycarboxamido-3-methanesulfonyloxy-4-(N-chloroacetylcarbamoyloxy)-butanamide 0.25 g (53%).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:14])=[CH:7][C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:23]([O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:14])=[CH:7][C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1)[CH:22]=[CH2:21]
Reactant: Cc1cc(=O)oc2c(C)c(O)ccc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(C)cc(=O)oc2c1C
Yield: 102.9 %

Procedure:
7-Hydroxy-4,8-dimethylcoumarin (91.075 g, 0.479 mol), anhydrous K2CO3 (302.9 g, 2.190 mol), and allyl bromide (217.1 mL, 2.51 mol) were added to 2.5 L of reagent grade acetone. The milky mixture was refluxed for eight hours with overhead stirring, filtered, and the filtrate was concentrated to dryness with the rotary evaporator to obtain 7-allyloxy-4,8-dimethylcoumarin (113.5 g, 0.493 mol, 103%). The crude product melted at 94.0°-100° C. (lit. mp 108° C.) and was used in the next step.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C@H:8]([OH:24])[CH2:9][NH:10][C:11]([CH3:23])([CH3:22])[CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[C:4]([F:27])[C:3]=1[F:28].C(#N)CC.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.[C:55]([O:59][CH2:60][CH3:61])(=[O:58])[CH:56]=[CH2:57]>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[CH2:60]([O:59][C:55](=[O:58])/[CH:56]=[CH:57]/[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C@H:8]([OH:24])[CH2:9][NH:10][C:11]([CH3:23])([CH3:22])[CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[C:4]([F:27])[C:3]=1[F:28])[CH3:61]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(CC1Cc2ccccc2C1)NC[C@@H](O)COc1ccc(Br)c(F)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(OC[C@H](O)CNC(C)(C)CC2Cc3ccccc3C2)c(F)c1F
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A 150 mL sealed tube was charged with a stirring bar, (R)-1-(4-Bromo-2,3-difluorophenoxy)-3-(2-indan-2-yl-1,1-dimethyl-ethylamino)-propan-2-ol (3.06 g) 1 and propionitrile (70 mL). To this was added Pd(OAc)2 (0.151 g), P(O-tol)3 (0.82 g), ethyl acrylate (1.35 g), triethylamine (2.73 g) sequentially and deoxygenated the reaction by bubbling nitrogen for 15 minutes. The sealed tube was capped tightly and immersed into a preheated (120° C.) oil bath. The reaction was heated at this temperature for 12 hrs. Cool to ambient temperature and concentrated under reduced pressure. The crude residue was purified by flash column chromatography eluting initially with 50% EtoAc in hexanes and 100% EtOAc. At this time the eluting solvent mixtures were switched to 100% dichloromethane, 5% MeOH in dichloromethane followed by 8% MeOH in dichloromethane. The product was collected and concentrated to get the desired product (2.40 g, 75%) as pale yellow foam. MS (ES) m/z 474 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:17]=2)=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=3)[N:17]=2)=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cncc(/C=C/c3ccc(C(F)(F)F)cc3)n2)sc1C(=O)NCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cncc(CCc3ccc(C(F)(F)F)cc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
To a solution of 4-methyl-2-{6-[(E)-2-(4-trifluoromethyl-phenyl)-vinyl]-pyrazin-2-yl}-thiazole-5-carboxylic acid benzylamide (40 mg, 0.08 mmol, 1.0 equiv) in ethyl acetate/ethanol (1:1) was added Pd(OH)2 (10 mg, 20%). The flask was first purged with nitrogen, then with hydrogen. The reaction mixture was stirred at ambient temperature for 3 hr and monitored by LCMS. Upon completion, the reaction mixture was diluted with ethyl acetate, filtered through Celite and concentrated in vacuo. The crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford 4-methyl-2-{6-[2-(4-trifluoromethyl-phenyl)-ethyl]-pyrazin-2-yl}-thiazole-5-carboxylic acid benzylamide (20 mg, 50%). 1H NMR (400 MHz, CD2Cl2) δ 9.16 (s, 1H), 8.39 (s, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.28-7.37 (m, 7H), 6.25 (bs, 1H), 4.60 (d, J=8.0 Hz, 2H), 3.19 (apparent s, 4H), 2.72 (s, 3H); HRMS (M+H)+=483.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][C:24]1=[O:33]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][C:24]2=[O:33])[CH2:13][CH2:12]1
Reactant: O=C1CCc2ccccc2N1CCCCCBr
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Product: Cl
Product: O=C1CCc2ccccc2N1CCCCCN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1

Procedure:
from 5-chloro-3-(piperidin-4-yl)-1H-indole and 1-(5-bromopentan-1-yl)-3,4-dihydroquinolin-2(1H)-one. Mp 206-209° C. 1H NMR (DMSO-d6): 1.30-1.40 (m, 2H); 1.55-1.65 (m, 2H); 1.70-1.80 (m, 2H); 2.00-2.15 (m, 4H); 2.55 (t, 2H); 2.85 (t, 2H); 2.95-3.10 (m, 4H); 3.10-3.25 (m, 1H); 3.55 (d, 2H); 3.90 (t, 2H); 7.00 (t, 1H); 7.05 (d, 1H); 7.15 (d, 1H); 7.20-7.30 (m, 3H); 7.40 (d, 1H); 7.75 (s, 1H); 11.20 (broad s, 1H); 11.15 (s, 1H). MS m/z: 450 (MH+), 299.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[C:16]([C:21]([OH:23])=O)=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12].C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[C:16]([C:21]([Cl:27])=[O:23])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(-c2ccccc2C(=O)O)cc(OC)c1OC
Agent: N#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2C(=O)Cl)cc(OC)c1OC
Reaction time: 2 h

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve 3′,4′,5′-Trimethoxy-biphenyl-2-carboxylic acid (56) (54 mg, 0.18 mmol) in anhydrous DCM (1.3 mL) and add anhydrous DMF (1 drop, cat. amount). Then add slowly oxalyl chloride (21 μL, 0.24 mmol) by keeping temperature at ca. 20° C. with a water bath and stir the turbid mixture for additional 2 h at it Remove solvent and dry in vacuum to obtain crude 3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl chloride (57) as a yellow solid. No further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2.BrCCCCCC(Cl)=O.Cl>O1CCOCC1>[NH:14]1[C:15]2[C:11](=[CH:10][C:9]([N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:2]3=[O:1])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N3CCCCCC3=O)ccc21
Agent: Cl
Agent: O=C(Cl)CCCCCBr
Solvent: C1COCCO1
Product: O=C1CCCCCN1c1ccc2c(c1)CCN2
Temperature: 25 °C
Yield: 99.2 %

Procedure:
Part A. To tert-butyl 5-(2-oxo-hexahydro-1H-azepin-1-yl)-1-indolinecarboxylate (140 mg, 0.42 mmol) that had been prepared as in Part C of Example 15 using 6-bromohexanoyl chloride instead of 5-bromovaleryl chloride was added 10 mL of 4.0 M HCl in dioxane. The resulting solution was maintained at rt under N2 for 2 h and was then concentrated. The resulting residue was dissolved in mL of EtOAc, and the organic layer was washed with saturated aqueous NaHCO3. The aqueous layer was washed with EtOAc (2×50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford 1-(2,3-dihydro-1H-indol-5-yl)hexahydro-2H-azepin-2-one (96 mg, 100%) as a brown oil. LC/MS (ESI+): 231.2 (M+H)+. 1H NMR (CDCl3) δ 6.9 (s, 1H), 6.79 (d, 1H), 6.76 (d, 1H), 3.98 (br s, 1H), 3.66 (br m, 2H), 3.52 (t, 2H), 3.01 (t, 2H), 2.65 (br s, 2H), 1.78 (br s, 6H).
Reaction SMILES: [H-].[Na+].C([C:5]([CH2:14][CH3:15])(P(=O)([O-])[O-])[C:6]([O:8][CH3:9])=[O:7])C.[C:16]([SiH2:20][O:21][C:22]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:23]1[CH2:27][CH2:26][C:25](C)(C=O)[C:24]1(C)[CH3:31])([CH3:19])([CH3:18])[CH3:17].O.[CH2:46]1COCC1>>[CH3:9][O:8][C:6](=[O:7])[CH:5]=[CH:14][C:15]1([CH3:46])[CH2:26][CH2:27][CH:23]([C:22]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:21][SiH2:20][C:16]([CH3:18])([CH3:19])[CH3:17])[C:24]1([CH3:25])[CH3:31]
Reactant: CCC(CC)(C(=O)OC)P(=O)([O-])[O-]
Reactant: C1CCOC1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C1CCC(C)(C=O)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C=CC1(C)CCC(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)C1(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a suspension of NaH (60% dispersion in petroleum ether; 1.47 g, 36.7 mmole) in dry THF (50 mL) at 0° C. was added dropwise diethylmethoxy-carbonylmethylphosphonate (6.88 mL, 36.71 mmole) over a period of 10 minutes. The solution was stirred at 0° C. for 35 minutes (color change to pale yellow) and 3-(tert-butyldiphenylsilanyloxymethyl)-1,2,2-trimethyl-cyclo-pentanecarbaldehyde (4) (10.0 g, 24.47 mmole) in dry THF (20 mL) was added dropwise over a period of 20 minutes. The reaction mixture was stirred at 0° C. for 3 hours and poured into cold water (500 mL). The aqueous layer was extracted with Et2O (4×100 mL) and the combined organic layers were dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was purified over a short column of silica (n-hexane/ethyl acetate, 9:1) and further purified over silica (n-hexane/ethyl acetate, 95:5) to afford 11.15 g (98% yield) of the desired intermediate (5) as a colorless oil which was characterized as follows:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[OH-].[Na+].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9]>O>[C:4]([CH2:3][NH:2][S:17]([C:14]1[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=1)(=[O:18])=[O:19])#[N:5]
Reactant: N#CCN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a stirred solution of 27.8 g (0.3 moles) aminoacetonitrile hydrochloride in 200 ml water, 24 g (0.3 moles) sodium hydroxide (50% aqueous) were added. The resulting mixture was cooled to about 20° C. with an ice bath. The ice bath was removed; then 22.2 g (0.1 mole) 4-nitrobenzenesulfonyl chloride were added. The reaction mixture was stirred 18 hours at ambient temperature. The solids were filtered. The resulting wet cake was crystallized from 50 ml ethanol. The solids were dried in vacuo to give 17.5 g of the above-identified product as a dark-yellow solid, melting point 115°-120° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][NH:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])([CH3:4])([CH3:3])[CH3:2].[O:40]1[CH2:45][CH2:44][CH:43](O)[CH2:42][CH2:41]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH:43]4[CH2:44][CH2:45][O:40][CH2:41][CH2:42]4)=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][NH:32][C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCOCC1
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccc(OC3CCOCC3)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-[4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (120 mg, 0.223 mmol, Example 406), tetrahydro-pyran-4-ol (22.7 mg, 0.223 mmol), triphenylphosphine (58.4 mg, 0.223 mmol) and toluene (10 mL) was treated dropwise with DIAD (45 mg, 0.223 mmol). The mixture was stirred under N2 at ambient temperature for 16 h and concentrated. The crude product was purified by radial chromatography (10-70% EtOAc/hexanes) to give 3-[2-(isopropoxycarbonylamino-methyl)-4-(2-{5-methyl-2-[4-(tetrahydro-pyran-4-yloxy)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionic acid tert-butyl ester. The ester product was dissolved 4M HCl/dioxane (5 mL), stirred for 16 h and concentrated to give the title compound: MS [ES] m/z 525 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]([CH3:15])[C:7](=[O:16])[C:6]=2[CH:17]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:18][C:14]1[N:13]=[CH:12][N:11]2[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=3[C:7](=[O:16])[N:8]([CH3:15])[CH2:9][C:10]=12
Reactant: CN1Cc2cncn2-c2ccc(F)cc2C1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(Cl)ncn2-c2ccc(F)cc2C1=O

Procedure:
2.31 g (10 mmol) of 8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 1.47 g (11 mmol) of N-chlorosuccinimide are heated to 100° for 30 minutes in dimethylformamide. Subsequently, the mixture is poured into water and extracted several times with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. The residue is recrystallized from ethyl acetate and yields 3-chloro-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 217°-218°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][CH2:14][C:9]21[CH2:13]CC[CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20]C(N)(CC)CN.CC(C)(O)C#N>>[CH2:1]([N:8]1[CH2:17][C:16]([CH2:18][CH3:20])([CH3:19])[NH:15][CH2:14][C:9]1([CH3:10])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(Cc2ccccc2)C2(CCCC2)CN1
Reactant: CCC(C)(N)CN
Agent: CC(C)(O)C#N
Product: CCC1(C)CN(Cc2ccccc2)C(C)(C)CN1

Procedure:
1-Benzyl-5-ethyl-2,2,5-trimethyl-piperazine was synthesized in analogy to 6-benzyl-8,8-dimethyl-6,9-diaza-spiro[4.5]decane starting from 2-methylbutane 1,2-diamine and acetone cyanohydrin.
Reaction SMILES: N[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([OH:14])[C:5]([N+:6]([O-:8])=[O:7])=[C:4](N)[C:3]=1[N+:16]([O-:18])=[O:17].[OH-:19].[Na+].Cl.[OH2:22]>>[N+:16]([C:3]1[C:2]([OH:19])=[C:10]([N+:11]([O-:13])=[O:12])[C:9]([OH:14])=[C:5]([N+:6]([O-:8])=[O:7])[C:4]=1[OH:22])([O-:18])=[O:17]
Reactant: O
Reactant: [OH-]
Reactant: Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Product: O=[N+]([O-])c1c(O)c([N+](=O)[O-])c(O)c([N+](=O)[O-])c1O
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Diaminopicric acid (0.100 g, 0.386 mmol) is suspended in water (6.85 ml) and a 50% aqueous solution of sodium hydroxide (0.65 ml,12.5 mmol) is added. The suspension is stirred for 0.5 hr in a heated water bath (98–100° C.) to produce an orange-red suspension which is cooled to 4° C. Addition of cold 12N hydrochloric acid (4 ml) produces a deep yellow suspension that is heated to solution. Cooling to 4° C. produces orange-yellow crystals (needles) that are collected, washed with cold 3N hydrochloric acid and dried to give trinitrophloroglucinol (0.085 g) in 84% yield. The IR spectrum for this material corresponds to that for known trinitrophloroglucinol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][CH3:25])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1>FC(F)(F)C(O)=O.O.O=[Pt]=O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][CH3:25])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1
Reactant: CNCCOCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNCCOCCn1c(CCOC)nc2c(N)nc3c(c21)CCCC3
Reaction time: 96 h
Yield: 74.6 %

Procedure:
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine (4.22 g, 12.3 mmol) was dissolved in 25 mL of trifluoroacetic acid and treated with PtO2 (0.5 g). The reaction mixture was shaken under H2 (3 Kg/cm2). After 4 d, an additional 0.5 g of PtO2 was added and hydrogenation was continued for an additional 3 d. The reaction was then filtered through Celite and concentrated under reduced pressure to give a yellow oil. The yellow oil was dissolved in 50 mL of H2O and extracted with 50 mL of CHCl3. The organic portion was removed and discarded. The aqueous portion was then made basic (pH˜12) by addition of 10% NaOH solution. This was then extracted with CHCl3 (6×50 mL) and the combined organic layers were dried over Na2SO4 and concentrated to a brown oil. The brown oil was dissolved in 100 mL of hot MeOH and treated with 1 g of activated charcoal. The hot solution was filtered through Celite and concentrated to dryness. The resulting gummy solid was concentrated several times with Et2O to give 3.19 g of 2-(2-methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder.
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26])(OC(C)(C)C)=O.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:8][C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1S,2R,3S,5R)-3-(di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (0.55 g, 1.09 mmol) in DCM (4 mL) is treated with TFA (2 mL) and stirred at RT. After 2 hours, the solvent is removed in vacuo to yield the title compound which is used in the next step without further purification. MS (ES+) m/e 304 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]=O>[NH2:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]([C:9]#[N:10])=[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:7]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd]Cl
Agent: O=[Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(-c2ccccn2)c1C#N
Temperature: 100 °C
Yield: 20.1 %

Procedure:
To a stirred solution of 600 mg (2,45 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 12 ml dry DMF under argon at room temperature were added 1.08 g (2.94 mmol) 2-(tributylstannyl)pyridine, 86 mg (0.12 mmol) bis(triphenylphosphine) palladium(II) chloride and 195 mg (2,45 mmol) copper(II) oxide. The reaction mixture was heated at 100° C. for 16 h, then cooled to room temperature, 2 g of kieselgel added, and the mixture concentrated in vacuo. Flash chromatography (hexane then 1/8 ethyl acetate/hexane) followed by trituration in ether/hexane afforded 120 mg (20%) 2-amino-4-methylsulfanyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile as an off-white crystalline solid. EI-MS m/e (%): 243 (M+, 95), 242 ([M—H]+, 100).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([CH2:7][CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])[CH3:3].[H-].[Na+].[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:26]Br.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH2:17]([O:16][C:14]([C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:22][C:23]1[CH:24]=[C:25]([CH3:26])[CH:28]=[C:29]([CH3:31])[CH:30]=1)[CH2:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:19])=[O:6])=[O:15])[CH3:18]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)OCC
Reactant: Cc1cc(C)cc(CBr)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)(Cc1cc(C)cc(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 13.8 g (50.2 mMol) of diethyl [(1,1-dimethyl-ethoxycarbonyl)methyl]-malonoate in 400 ml of anhydrous tetrahydrofuran, 2.3 g (52.7 mMol) of sodium hydride was added whilst being externally cooled with iced water. After stirring for 30 minutes, and maintaining a reaction temperature of 0 to +5° C., the solution of 10.0 g (50.2 mMol) of 3,5-dimethylbenzylbromide in 80 ml tetrahydrofuran was added dropwise and the mixture allowed to warm to room temperature within 14 hours. The reaction mixture was freed from the solvent in vacuo, 200 ml of 10% citric acid was added to the residue and the resulting mixture was thoroughly extracted with ethyl acetate. After the usual working up, the combined extracts yielded 19.7 g (100% of theory) of a colourless oil of Rf=0.67 (eluant:dichloromethane), which was used in the following steps without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].O>CS(C)=O>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1
Reactant: COc1nc2cc(F)ccc2nc1Cl
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2nc3ccc(F)cc3nc2OC)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
To 2-chloro-6-fluoro-3-methoxyquinoxaline (4.00 g, 18.8 mmol) dissolved in dimethylsulfoxide (40 ml), 2,4-dimethoxybenzylamine (7.86 g, 47.0 mmol) was added at room temperature. The mixture was stirred at room temperature for 24 hours and then water was added thereto. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (6:1) mixture and concentration gave 4.45 g of the titled compound (yield, 92%).