Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([OH:9])=[CH:6][C:7]=1[CH3:8].[ClH:11]>[N+](C)([O-])=O>[Cl:11][C:3]1[C:4]([CH3:10])=[C:5]([OH:9])[C:6]([C:6]2[C:5]([OH:9])=[C:4]([CH3:10])[C:3]([Cl:11])=[CH:2][C:7]=2[CH3:8])=[C:7]([CH3:8])[CH:2]=1
Reactant: Cl
Reactant: Cc1cc(Cl)c(C)cc1O
Solvent: C[N+](=O)[O-]
Product: Cc1cc(Cl)c(C)c(O)c1-c1c(C)cc(Cl)c(C)c1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mechanically-stirred mixture of 71.4 g (0.458 mol) of 4-chloro-2,5-xylenol and 120 mL of nitromethane was added 94 g (0.59 mol) of anhydrous ferric chloride in portions over about 20 minutes with cooling to maintain the temperature below 35° C. The mixture was stirred for an additional 3 hours and then 300 mL of ice water containing 50 mL of concentrated HCl was added, followed by 300 mL of hexanes. The mixture was filtered, and the solids were washed with water and hexanes and dried in vacuo to give 51.0 g of product. The organic phase was separated from the filtrate, washed with water, and concentrated; the residue was then slurried in hexanes and filtered to give another 11 g of product. The total yield was thus 62 g (87%) of a tan solid (mp 148-155° C.). Additional purification to remove traces of iron helps facilitate the subsequent reductive dechlorination. Purification could be accomplished by dissolving in ethyl acetate, washing this solution with aqueous ethylenediamine-tetraacetic acid disodium salt (EDTA-2Na, EDTA=ethylenediaminetetraacetic acid), drying (MgSO4), concentration and washing with hexanes to afford off-white material with mp 164° C. 1H-NMR (CDCl3) δ 1.98 (s, 3H), 2.25 (s, 3H), 4.60 (s, 1H), 7.25 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Reactant: Nc1nc2c(Br)cccn2n1
Product: CS(=O)(=O)c1ccccc1-c1cccn2nc(N)nc12

Procedure:
8-(2-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.50 g, 2.3 mmol) and 2-(methylsulfonyl)phenylboronic acid (0.56 g, 2.8 mmol) in a manner analogous to Step 2c. The reaction product was isolated as a pale yellow solid (0.249 g, 37%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.56 (d, J=6.6 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.36 (d, J=7.1 Hz, 1H), 6.93 (d, J=6.9 Hz, 1H), 5.99 (s, 2H), 3.16 (s, 3H). MS=289 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9](OC)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.[CH2:17]([NH2:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9]([NH:25][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1
Reactant: COc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: NCCc1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)cc1NCCc1ccccc1
Temperature: 80 °C

Procedure:
8-Chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.5 g) was treated with 5 mL of phenethylamine, and the mixture was heated to 80° C. for 1 hour. The reaction mixture was filtered and the solid recrystallized from 5 mL hot dimethylformamide and water. The solid was filtered, washed (water) and vacuum dried (100° C., 15 Pa) to give the title compound (0.329 g); mp 284.4°-286.9° C.; NMR: 5.89 (s,1); MS: m/z=327(M+1). Analysis for C18H15ClN2 O2.0.2 H2O: Calculated: C, 65.44; H, 4.70; N, 8.48; Found: C, 65.42; H, 4.72; N, 8.62.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: CS(=O)(=O)OCCc1ccc(Cl)cc1
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCc3ccc(Cl)cc3)n2)ccc1F
Yield: 56.3 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 2-(4-chlorophenyl)ethanol methanesulfonate were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as a pale yellow solid (yield: 56.3%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH:19]([C@H:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[N:22]1[CH2:28][C:29]#[C:30][CH2:31][O:32][CH2:33][C:34]#[N:35])=O>C1COCC1>[O:27]=[C:23]1[CH2:24][CH2:25][CH2:26][C@H:21](/[CH:19]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:22]1[CH2:28][C:29]#[C:30][CH2:31][O:32][CH2:33][C:34]#[N:35]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: N#CCOCC#CCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCOCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 18 mg, 0.45 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (110 mg, 0.45 mmol) in THF (1.5 mL) at 0° C. After 1 h at 0° C., a solution of [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetonitrile (0.50 mmol, crude from step 5) in THF (1.5 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with aqueous acetic acid (50%, 10 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10% →40% EtOAc/CH2Cl2, gradient) afforded 75 mg (48%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][N+:3]=1[O-]>C(O)(=O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:11])=[CH:4][N:3]=1
Reactant: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc(N)c(C)cn1
Temperature: 60 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
A mixture of 2,5-dimethyl-4-nitropyridine N-oxide (7.0 g, 41.7 mmol) and 10% Pd/C (1.2 g) in acetic acid (60 mL) was stirred under hydrogen at 60° C. for 18 h. The solution was cooled, filtered, and diluted with water (100 mL). The aqueous mixture was neutralized with solid sodium carbonate. The solution was extracted with DCM (250 mL×5), and the combined organic phase was dried with anhydrous sodium sulfate and concentrated to give 4.6 g of the product as a yellow solid. MS (ESI): m/z 123.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[NH4+].[Cl-].[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[CH:19]=1
Reactant: CC1(C)OB(c2cnccc2Cl)OC1(C)C
Reactant: Cc1nc(N)cc(Cl)n1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(N)cc(-c2cnccc2Cl)n1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
A mixture of 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (239 mg, 998 μmol, Combi-Blocks, Inc., San Diego, Calif.), 6-chloro-2-methylpyrimidin-4-amine (143 mg, 998 μmol), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium (II) (81 mg, 100 μmol), cesium carbonate (160 μl, 1996 μmol) in dioxane (2 mL) and water (0.5 mL) was stirred at 100° C. for 10 min. The mixture was cooled down to room temperature. The reaction mixture was diluted with saturated NH4Cl (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL), dried over Na2SO4, filtered, concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with THF to give 6-(4-chloropyridin-3-yl)-2-methylpyrimidin-4-amine (32 mg, 15% yield). 1H NMR (300 MHz, MeOH) δ 8.66 (s, 1H); 8.57 (d, J=5.41 Hz, 1H); 7.66 (d, J=5.26 Hz, 1H); 6.64 (s, 1H); 2.04 (s, 3H). m/z (ESI, +ve ion) 221 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([Br:27])=[CH:19][CH:18]=2)=[O:16])=[O:13])=[CH:4][CH:3]=1.[C:28]1([C:38]([OH:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.BrBr.[Cl:43]Cl>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([Br:27])=[CH:19][CH:18]=2)=[O:16])=[O:13])=[CH:4][CH:3]=1.[Cl:43][C:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]([C:38]([OH:40])=[O:39])=[CH:29][CH:30]=1
Reactant: ClCl
Reactant: O=C(O)c1cccc2ccccc12
Agent: BrBr
Agent: O=C(OC(=O)c1ccc(Br)c2ccccc12)c1ccc(Br)c2ccccc12
Product: O=C(O)c1ccc(Cl)c2ccccc12

Procedure:
A process for the preparation of 4-bromo-naphthalic acid anhydride by bromination of an alkali metal salt of naphthalic acid in an aqueous medium at a pH of 6.8 to 9 by dropwise adding 0.55 to 0.65 mol of bromine per mol of naphthalic acid and oxidizing the bromine at the same pH-value with chlorine. By this process 4-bromo-naphthalic acid anhydride can be obtained in a quantitative yield whereby the formation of 4-chloro-naphthalic acid is avoided.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:4])[CH3:2].ClS([N:29]=[C:30]=O)(=O)=O>O1CCCC1>[C:30]([C:15]1[N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:13]([C:10]2[CH:9]=[CH:8][C:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:12][CH:11]=2)=[CH:17][CH:16]=1)#[N:29]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCS(=O)(=O)Nc1ccc(-c2cccn2C(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
tert-Butyl 2-{4-[(ethylsulfonyl)amino]phenyl}-1H-pyrrole-1-carboxylate (3.0 g, 8.58 mmol) was dissolved in tetrahydrofuran (85 mL) and cooled to −78° C., followed by the slow addition of chlorosulfonyl isocyanate. After tert-Butyl 2-{4-[(ethylsulfonyl)amino]phenyl}-1H-pyrrole-1-carboxylate was consumed, dimethyl formamide (6.86 mL) was added and the solution allowed to warm to room temperature. After 2 hours, the mixture was cooled and partitioned between water and diethyl ether. The combined organic layers were dried over magnesium sulfate, and concentrated. The residue was purified by silica gel flash chromatography (hexane/ethyl acetate; 7:3) to afford the title compound (1.84 g, 57%). The title compound was used immediately in the next step.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([OH:11])=[O:10].C(=O)([O-])[O-].[Na+:25].[Na+].C(O)C>C1(C)C=CC=CC=1.CO.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:6]1[CH:7]=[CH:8][C:3]([C:15]2[CH:16]=[CH:17][C:12]([C:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)=[CH:4][CH:5]=1.[Na+:25]
Reactant: Clc1ccncc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C([O-])c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Yield: 41 %

Procedure:
A solution of 4-chloropyridine hydrochloride (3.00 g, 20.0 mmol), 4-carboxybenzeneboronic acid (4.97 g, 30.0 mmol), 1 M aqueous sodium carbonate solution (50 mL), 1,4-bis(diphenylphosphino)butane palladium(II) dichloride (300 mg, 0.70 mmol), and ethanol (10 mL) in toluene (40 mL) was heated at reflux for 16 h. The mixture was diluted with methanol and filtered through diatomaceous earth. The filtrate was concentrated in vacuo and the pH was adjusted to 14 by the addition of 1 N aqueous sodium hydroxide. After heating the filtrate to boiling, the insoluble material was removed by filtration, and the resulting filtrate was allowed to cool to room temperature. The resulting precipitate was collected by filtration to yield 1.83 g (41%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:13][CH2:12]2)[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:65][CH2:66][CH2:67][CH2:68][N:69]1[CH2:73][CH2:72][O:71][C:70]1=[O:74]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:13][CH2:12]2)[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:3]=1[C:4]([NH:65][CH2:66][CH2:67][CH2:68][N:69]1[CH2:73][CH2:72][O:71][C:70]1=[O:74])=[O:6]
Reactant: NCCCN1CCOC1=O
Reactant: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)O)cc2[N+](=O)[O-])CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCOC3=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
In a 40 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the 2-chloro-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid 1d (141.40 mg, 0.38 mmol) was taken up in clean, dry N,N-dimethylformamide (3.00 ml, 38.74 mmol) and the mixture was stirred together at room temperature under nitrogen atmosphere until all solids were taken up into solution. To this was added the HATU (171.70 mg, 0.45 mmol) followed by the N,N-diisopropylethylamine (0.20 ml, 1.15 mmol) and the mixture was once again stirred until all solids were in solution. Finally, the 3-(3-amino-propyl)-oxazolidin-2-one 15a (71.22 mg, 0.49 mmol) was added in one portion and the reaction was allowed to stir at room temperature overnight. The reaction was diluted with 10 ml of water and 10 ml of ethyl acetate. The layers were then separated and the product was extracted from the solution using ethyl acetate (3×15 ml). The organic phases were combined, washed with brine (1×25 ml) and saturated aqueous lithium chloride solution (2×25 ml). The solution was dried over Na2SO4; the solution was decanted and the solvent was removed under reduced pressure. The product was then purified using silica gel column chromatography, eluting a gradient of 100% dichloromethane to 10% MeOH in dichloromethane. The product, 2-chloro-5-nitro-N-[3-(2-oxo-oxazolidin-3-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 15b (170.60 mg, 0.34 mmol), was isolated as an off-white solid and was carried on without further purification. LCMS=501 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][NH:16][C@H:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([O:32]CCC)=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([N:16]([CH3:15])[C@H:17]3[CH2:36][N:21]4[C:22]5[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]4[CH2:19][CH2:18]3)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCC1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C1(c2ccc(F)cc2)CCC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 1-(4-fluorophenyl)cyclobutanecarboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 435.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:20][CH2:21][NH:22]S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([C:17](=[O:19])[CH3:18])=[CH:11][CH:10]=3)(=[O:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].C1(S)C=CC=CC=1.C(Cl)(Cl)Cl.CO>CC#N.CO>[NH2:22][CH2:21][CH2:20][N:8]1[C:9]2[CH:10]=[CH:11][C:12]([C:17](=[O:19])[CH3:18])=[CH:13][C:14]=2[C:15]2[C:7]1=[CH:6][CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:16]=2
Reactant: CC(=O)c1ccc2c(c1)c1cc(C(C)=O)ccc1n2CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc2c(c1)c1cc(C(C)=O)ccc1n2CCN

Procedure:
Compound 52 (4.11 g, 8.58 mmol) was dissolved under reflux in a mixture of CH3CN (150 mL) and methanol (50 mL). Then, Cs2CO3 (8.4 g, 25.78 mmol) was added and at once PhSH (2.6 mL, 25.48 mmol) was poured in. The resulting mixture was refluxed for 2.5 h (TLC monitoring, eluent: chloroform-methanol, 9:1) and evaporated to dryness. Then, water and a solution of HCl were added. As a result, all the solid products were dissolved. The acidic aqueous solution was extracted with ethyl acetate until the latter ceased to become yellow. The aqueous layer was neutralized with a saturated solution of NaHCO3, extracted with a CH2Cl2-MeOH mixture (4:1), and the extract was evaporated. The residue was washed off with MeCN and washed with ether. Yield of 53: 1.25 g (50%) as beige crystals.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.[CH3:14][C:15]1[C:23]2[C:22]([N:24]3[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]3)=[N:21][CH:20]=[N:19][C:18]=2[S:17][C:16]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(O)C.CS(C)=O>[OH:13][CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH:2]([OH:1])[CH2:3][NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:22]2[C:23]3[C:15]([CH3:14])=[C:16]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[S:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:25][CH2:26]1
Reactant: OCc1cccc(OCC2CO2)c1
Reactant: Cc1c(-c2ccccc2)sc2ncnc(N3CCC(N)CC3)c12
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1c(-c2ccccc2)sc2ncnc(N3CCC(NCC(O)COc4cccc(CO)c4)CC3)c12
Yield: 36 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 35 h), using 150 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give the title compound with 36% yield upon purification by prep. HPLC (reversed phase).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1.[I:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH:20]=O.II>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[N:9]=[C:20]([C:13]3[C:14]([O:18][CH3:19])=[N:15][CH:16]=[CH:17][C:12]=3[I:11])[NH:8][C:6]=2[CH:7]=1
Reactant: COc1nccc(I)c1C=O
Reactant: Cc1cc(Br)cc(N)c1N
Agent: II
Solvent: CO
Product: COc1nccc(I)c1-c1nc2c(C)cc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a solution of 5-bromo-3-methyl-1,2-phenylenediamine (4 g, 19.9 mmol) in methanol (80 mL) was added 4-iodo-2-methoxy-pyridine-3-carbaldehyde (5.23 g, 19.9 mmol) in methanol (20 mL) dropwise at 0° C. The resulting slurry was stirred for 30 min at room temperature. Then iodine (2.53 g, 9.95 mmol) in methanol (20 mL) was added via a dropping funnel. After 14 h, the reaction mixture was concentrated in vacuo, diluted with 5% Na2S2O3, and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. After removal of solvent, the residue was purified by careful flash chromatography (20% EtOAc/hexane) to yield the title compound (4.05 g, 46%) as a yellow foam. 1H NMR (300 MHz, CDCl3) δ 7.86 (1H, d, J=5.31 Hz), 7.53 (1H, d, J=5.3 Hz), 7.26 (2H, broad s), 3.91 (3H, s), 2.63 (3H, s). LCMS (M+H)+ m/z 444 (t=1.39 min.).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][N:26]3[CH3:31])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(OCC)(=O)C.O>CN(C)C=O>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[C:25]([Cl:1])[N:26]3[CH3:31])[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cnc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(Cl)nc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.8 %

Procedure:
N-chlorosuccinimide (1.25 g) was added to a solution of 4-(9-methyl-9H-purin-6-yl)-piperazine-1-carboxylic acid t-butyl ester (2.70 g) in N,N-dimethylformamide (30 mL), and this was stirred at room temperature for 20 hours. Ethyl acetate (200 mL) and water (50 mL) were added, the organic layer was washed twice with 50 mL of water and then once with 50 mL of saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The organic layer was filtered and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, and the ethyl acetate:hexane 4:1 fraction gave the title compound (1.97 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][OH:13])[CH:8]=[CH:7][CH:6]=2>ClCCl.[O-2].[Mn+4].[O-2]>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[C:10]=2[CH:11]=1
Reactant: Cc1cnc2cccc(CO)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cnc2cccc(C=O)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
30.0 g (173 mmol) of the compound from example 22A are taken up in 850 ml of dichloromethane, and 240.0 g of manganese(IV) oxide are added. The mixture is stirred at room temperature for 16 h and then filtered through kieselguhr. The latter is washed with dichloromethane, and the filtrate is concentrated in a rotary evaporator. Drying the residue results in 23.0 g (75% of theory) of the title compound.
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH:18][C@@H:19]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:20][N:21]1[C:26]2=[N:27][C:28]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)=[CH:29][C:30](=[O:31])[N:25]2[CH2:24][CH2:23][C:22]1([CH3:39])[CH3:38].C(N(CC)CC)C>ClCCl.O>[CH3:38][C:22]1([CH3:39])[CH2:23][CH2:24][N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)[N:27]=[C:26]2[N:21]1[CH2:20][C:19](=[O:18])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC1(C)CCn2c(nc(-c3ccncn3)cc2=O)N1C[C@@H](O)c1ccccc1
Solvent: CS(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCn2c(nc(-c3ccncn3)cc2=O)N1CC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 22.6 %

Procedure:
To a solution of 0.24 ml (3.3 mmol) of dimethyl sulfoxide in 3 ml of anhydrous dichloromethane at −780° C. was added 0.42 ml (2.93 mmol) of trifluoroacetic anhydride in 2 ml of anhydrous dichloromethane and the mixture allowed to stir at −78° C. for 20 min. 0.201 g (0.53 mmol) of 9-(2(S)-Hydroxy-2-phenyl-ethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one in 2 ml of anhydrous dichloromethane was added at −78° C. and stirring continued for 30 min. 0.62 ml (4.47 mmol) of triethylamine was added and the mixture allowed to stir at room temperature for 12 h. Water was added and the mixture extracted with ethyl acetate, the extracts were washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium chloride, dried and evaporated to give crude product. Purification by chromatography on silica gel eluting with ethyl acetate gave 0.045 g (23%) of pure product. Mp.: 203-205° C.