Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](Br)=[C:9]([S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=3)(=[O:14])=[O:13])[S:8][C:5]2=[N:6][CH:7]=1.C(O)C.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:27])[CH:33]=3)=[C:9]([S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=3)(=[O:14])=[O:13])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: N#Cc1cc(F)cc(S(=O)(=O)c2sc3ncc(N)cc3c2Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1cc(F)cc(S(=O)(=O)c2sc3ncc(N)cc3c2-c2cccc(Cl)c2)c1

Procedure:
5-Amino-3-bromo-2-(3-cyano-5-fluoro-benzenesulfonyl)-thieno[2,3-b]pyridine (1.25 g, 30 mmol) was dissolved in toluene (18 ml) and ethanol (20 ml) under argon atmosphere. To the solution Pd(PPh3)4 (175 mg, 0.15 mmol), 3-chlorophenylboronic acid (0.58 g, 37 mmol) and 2M solution of Na2CO3 (15 ml) was added. The reaction mixture was refluxed for 1 hour then it was filtered through celite and washed with toluene (2×5 ml). The filtrate was tightened in vacuum; water (13 ml) and ethyl acetate (13 ml) were added to the residue. It was separated and the water phase was extracted with ethyl acetate (2×5 ml). The organic phase was washed with water (5.0 ml), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (Kieselgel 60, ethyl acetate:hexane=2:1) to yield the title compound which was purified by stirring with methanol (5 ml) to give 0.84 g (63%) yellow amorphous material. LC-MS: (M+H)+ 444.2. 1H NMR (400 MHz, DMSO-d6, 25° C.): 5.68 (s, 2H); 6.80 (d, J=2.6 Hz, 1H); 7.13-7.22 (m, 2H); 7.53 (t, J=7.9 Hz, 1H); 7.56-7.65 (m, 3H); 8.24 (dm, J=8.4 Hz, 1H); 8.27 (d, J=2.6 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: N#Cc1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.1 g, 9.8 mmol) was dissolved in 100 mL dry diethyl ether under an argon atmosphere, added dry pyridine (3.3 mL, 32.5 mmol), cooled to 0° C. then added oxalyl chloride (1.4 mL, 16.3 mmol) dropwise. A precipitate forms immediately upon addition of oxalyl chloride and therefore reaction requires vigorous stirring. Stirred at 0° C. for one hour than at ambient temperature for 2 hours. Dry diethyl ether (100 mL) was added and the solids were filtered off, washing with more diethyl ether. The filtrates were concentrated, then redissolved in dry DCM under argon, cooled to 0° C., added 1 mL dry pyridine then added 4-amino-benzonitrile (0.96 g, 8.1 mmol) in one portion. Stirred at ambient temperature for 2 hours, concentrated, redissolved in ethyl acetate (250 mL), washed with 10% citric acid (3×100 mL), water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white foam. (2.4 g, 93%) APCI (AP−): 314.1 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1.[NH2:12][OH:13]>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]([NH:12][OH:13])=[NH:8])=[CH:5][N:4]=1
Reactant: NO
Reactant: CN(C)c1ccc(C#N)cn1
Solvent: CCO
Product: CN(C)c1ccc(C(=N)NO)cn1
Reaction time: 11 h

Procedure:
In a 100 ml round flask, 4.7 g (31.9 mmol) of 6dimethylamino-nicotinonitrile and 1.88 ml (31.9 mmol) of aqueous hydroxylamine (50%) are dissolved in 25 ml of ethanol. This mixture is reacted at 90° C. for 6 h. Then another 0.45 ml (8.1 mmol, 0.25 eq.) of hydroxylamine-solution is added. After 11 h at 90° C., the mixture is cooled and the solvent removed in vacuo. This yields the title compound as light yellow solid, which is used for the next step without purification. Mass spectrum: m/z (M+H)+: 181.0
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])/[C:12](O)=[O:13])=[CH:7][CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[OH:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:12](=[O:13])/[C:11](/[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:26][CH:27]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC/C(=C(\C(=O)O)c1ccc(OCOC)cc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC/C(=C(\C(=O)Nc1ccc(O)cc1)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
To a mixture of 3 (60 mg, 0.192 mmol), 4-aminophenol (23.0 mg, 0.211 mmol), 4-Dimethylaminopyridine (1.2 mg, 0.00982 mmol) and N,N-Diisopropylethylamine (37.2 mg, 0.287 mmol) in CH2Cl2 (2 ml) was added O-Benzotriazoyl-N,N,N′,N′-tetramethyluronium Hexafluorophosphate (76.5 mg, 0.202 mmol) under ice cooling, and the mixture was stirred at 0° C. for 5 min, and at room temperature for 15 h. The reaction was quenched with saturated aqueous NaHCO3 under ice cooling, and the whole was extracted with CHCl3, the organic layer was washed with brine, dried over Na2SO4, and then concentrated. Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 3:1 to 2:1) gave 6a (68%). 6a: colorless powder; 1H-NMR (CDCl3) δ 1.05 (3H, t, J=7.5 Hz), 2.77 (2H, t, J=7.5 Hz), 3.43 (3H, s), 5.09 (2H, s), 6.79 (4H, m), 7.00 (2H, d, J=8.8 Hz), 7.00 (1H, brs), 7.07 (2H, m), 7.15-7.22 (3H, m), 7.37 (2H, d, J=8.8 Hz).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH2:9]([OH:11])[CH3:10]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][O:11][CH:9]1[CH2:3][CH2:4][O:6][CH2:7][CH2:10]1)[CH3:8]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCO
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COC1CCOCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of tetrahydro-4H-pyran-4-one (1.0 g, 10.0 mmol) in cold (0° C.) THF is added 1.0M lithium aluminum hydride in THF (5 mL, 5.0 mmol). The reaction mixture is stirred at 0° C. for 15 min. followed by the sequential addition of water (0.190 mL), 5M sodium hydroxide (0.190 mL), and water (0.190 mL) and Et2O. The mixture is filtered, and the filtrate is evaporated to give tetrahydro-4H-pyran-4-ol, which is dissolved in dichloromethane (30 mL). To the solution is added rhodium (II) acetate dimer (44 mg) followed by ethyl diazoacetate (1.25 g, 11.0 mmol). The reaction mixture is stirred at RT for 40 min. The reaction mixture is diluted with ethanol, filtered through celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 1.67 g of the product 409. 1H NMR (CDCl3) δ 4.21 (q, 2H), 4.11 (s, 2H), 3.95 (dt, 2H), 3.59 (m, 1H), 3.42 (dt, 2H), 1.91 (m, 2H), 1.62 (m, 2H), 1.28 (t, 3H); MS: m/z 189 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[C:4]([CH3:30])[CH:3]=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:41]([O-])=[O:42])C=1.[CH2:44]([NH2:49])[C:45]([CH3:48])([CH3:47])[CH3:46]>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:41]([NH:49][CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:42])=[CH:3][C:4]=3[CH3:30])[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cc(N)ccc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Reactant: CC(C)(C)CN
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCC(C)(C)C)ccc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
3-((4-(4-Amino-2-methylbenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (100 mg, 0.24 mmol) and 4-nitrophenylchloroformate (49 mg, 0.24 mmol) were stirred in dichloromethane (2 mL) for 30 minutes. Neopentylamine (64 mg, 0.73 mmol) was added and the reaction stirred at room temperature for 2 hours. The reaction was concentrated under vacuum. The resulting residue was purified by acidic reverse phase HPLC to afford the title compound (31 mg). MS (ESI) m/z 522.7 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][NH2:13]>O>[CH3:12][NH:13][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN
Reactant: ClCc1nc2ccccc2o1
Solvent: O
Product: CNCc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
2-(Chloromethyl)benzoxazole (3.99 g, 23.8 mmol) was dissolved in aqueous methylamine (40 mL, 40 wt % in H2O) at 10° C. under a nitrogen atmosphere. After 20 minutes, the reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The organic phase was dried (MgSO4) and concentrated to afford crude product which was purified by flash column chromatography (5% methanol/dichloromethane) to afford 3.18 g (82%) of pure product as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:12]=2)=[N:6][CH:7]=1.O[C@H:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(OCC)(=O)C.C1COCC1>[O:23]=[C:19]1[C@H:18]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:12]=3)=[N:6][CH:7]=2)[CH2:22][CH2:21][NH:20]1
Reactant: COC(=O)c1cnc(-c2ccc(O)cn2)s1
Reactant: O=C1NCC[C@@H]1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(-c2ccc(O[C@@H]3CCNC3=O)cn2)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a round-bottomed flask was added methyl 2-(5-hydroxypyridin-2-yl)thiazole-5-carboxylate (400 mg), (S)-3-hydroxy-pyrrolidin-2-one (188 mg), PPh3 (443 mg), and THF (10 mL). DEAD (299 mg) was added dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours. After being diluted with ethyl acetate (50 mL), the organic layer was washed with water (20 mL×2) and brine (10 mL) and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, the residue obtained was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (4:1 to 1:3) to afford the subtitle compound. MS ESI+: m/z=320 [M-FH]+.
Reaction SMILES: C[C@:2]1([O:11][C:10]([CH2:14][OH:15])([CH2:12][OH:13])[C@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[OH:5])O>S(=O)(=O)(O)O>[OH:13][CH2:12][C@@:10]12[CH2:14][O:15][C@@H:2]([O:11]1)[C@H:4]([OH:5])[C@@H:6]([OH:7])[C@H:8]2[OH:9]
Reactant: C[C@@]1(O)OC(CO)(CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=S(=O)(O)O
Product: OC[C@@]12CO[C@@H](O1)[C@H](O)[C@@H](O)[C@H]2O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 39.6 %

Procedure:
Methyl 5-C-hydroxymethyl-α-L-arabino-hexopyranose (3) (59.0 g, 0.263 moles) is dissolved in 0.70M sulfuric acid (260 ml), and stirred at 100° C. for 90 minutes. The solution is cooled to room temperature and neutralized using an ion exchange resin (Amberlite IRA-400 (OH-). The resin is filtered off, and the filtrate is refluxed for 15 minutes with activated carbon (4.0 g). Carbon is removed with a glass fiber filter, and the filtrate is evaporated to dryness with ethanol. The white waxy residue is refluxed for 15 minutes with methanol (50 ml). The solution is stored overnight at 0° C. The product is filtered to yield 20.0 g (39.6%) of 1,6-anhydro-5-C-hydroxymethyl-β-L-altropyranose (4).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:8]=2[S:7](=[O:19])(=[O:18])[NH:6][C:5]=1[C:20]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:21])=[CH:16][CH:15]=[CH:14][CH:13]=3.[CH3:28]I>CO>[OH:3][C:4]1[C:9]2[CH:10]=[CH:11][C:12]3[C:17]([C:8]=2[S:7](=[O:19])(=[O:18])[N:6]([CH3:28])[C:5]=1[C:20]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:21])=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CI
Reactant: O=C(Nc1nccs1)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.4 %

Procedure:
3.15 ml of 1 N sodium hydroxide (3.15 millimols) were added dropwise to a suspension of 1.12 gm (3 millimols) of 4-hydroxy-N-(2-thiazolyl) 2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide in 50 ml of methanol and 1.7 gm (12 millimols) of methyl iodide, whereby a reddish solution was formed. The solution was stirred at room temperature for 72 hours and was then evaporated to dryness in vacuo. The residue was triturated with water, filterd off and recrystallized from ethylene chloride, yielding 0.47 gm (40.5% of theory) of 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 249°-250° C (decomp).
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=[O:3])[CH3:2].[C:31](Cl)(=O)CC>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:1](=[O:3])[CH2:2][CH3:31])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCC(=O)Cl
Product: CCO[C@H]1CN(C(=O)CC)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting propionyl chloride and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, DMSO) δ) 7.71, 7.50, 7.41, 6.00, 5.98, 4.68, 4.52, 4.22, 4.11, 3.85-3.39, 2.68, 2.37, 2.25, 1.24-0.85; HRMS (FAB) calcd for C23H30Cl2N4O2+H 465.1824, found 465.1825.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[N:27]=[C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][N:34]=[CH:33][C:32]=23)[CH:25]=[N:24][CH:23]=1>CN(C=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[N:30]1[N:31]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]2=[C:28]([C:26]2[N:27]=[C:22]([NH:1][C@@H:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)[CH:23]=[N:24][CH:25]=2)[CH:29]=1
Reactant: Clc1cncc(-c2cnn3ccncc23)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccncc34)n2)C1
Temperature: 100 °C
Yield: 43.5 %

Procedure:
Tert-butyl (3R)-3-aminopiperidine-1-carboxylate (0.41 g, 2.05 mmol), tris(dibencylidenoacetone)dipalladium(0) (0.034 g, 0.037 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene (0.043 g, 0.074 mmol) and cesium carbonate (0.848 g, 2.6 mmol) were added to a suspension of 3-(6-chloropyrazin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 29b, 0.43 g, 1.86 mmol)) in N,N′-dimethylformamide (10 mL) and the resulting mixture was purged with argon before being heated to 100° C. for 7 h. After cooling to ambient temperature, the reaction mixture was filtered though Celite®, eluting with methanol. The filtrate was evaporated and the residue was purified by flash chromatography (7:3 ethyl acetate/hexane to 100% ethyl acetate) to yield the title compound (0.320 g, 44%) as a greenish solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][CH2:31][CH2:32]Cl>CN(C=O)C.CCOC(C)=O>[Cl:30][CH2:31][CH2:32][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:11]2[O:10][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:13][C:12]=2[C:14]([NH2:16])=[O:15])=[CH:22][CH:21]=1
Reactant: ClCCCl
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide (0.100 g, 0.316 mmol) in DMF (5 ml) were added potassium carbonate (0.220 g, 1.58 mmol) and 1,2-dichloroethane (0.50 ml, 6.32 mmol). The reaction was heated to 130° C. via microwave irradiation and held at that temperature for 1 hour. The reaction was then diluted with EtOAc, washed with water and brine and dried over Na2SO4 before being concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using 0-50% EtOAc in hexane as eluant to afford 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.11 g, 0.29 mmol, 92%) as a white solid. LCMS (1) 2.25 min; m/z (ES+) 379/381.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].[Br:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:21]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:18]2[CH:19]=[C:20]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH:21]=[C:16]([Br:15])[CH:17]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: CC(C)COc1cc(Br)cc(B(O)O)c1
Reactant: COC(=O)COc1ccc(O)cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(Oc2cc(Br)cc(OCC(C)C)c2)cc1C

Procedure:
(4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (215 mg; 1.1 mmol), 3-Bromo-5-isobutoxy-phenylboronic acid (523.4; 1.9 mmol), copper(II) acetate (199 mg; 1.1 mmol), crushed molsieves (about 1 g) and triethylamine (0.46 ml; 3.3 mmol) was dissolved in dichloromethane (40 ml) and stirred over night. The reaction mixture was filtered through celite and evaporated to dryness. The crude product was purified by preparative HPLC (method B). Yield: 300 mg; 65%. HPLC-MS: m/z: 423.5 (M+); Rt: 2.71 min
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[NH:4][C:3]1=[O:29].[C:30]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Cl)=[CH:36][CH:35]=1)(=[O:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:30]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][N:4]2[C:5]3=[N:11][N:10]([CH2:12][C:13]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:16]=[CH:15][CH:14]=4)[C:9]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)=[C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3]2=[O:29])=[CH:36][CH:35]=1)(=[O:32])[CH3:31]
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3ccncc3)c2c1=O
Reactant: CC(=O)Oc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(Cn2c(=O)n(C)c(=O)c3c(-c4ccncc4)n(Cc4cccc5ccccc45)nc32)cc1

Procedure:
This compound was synthesized by the reaction of 5-methyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 4-(chloromethyl)phenyl acetate using potassium carbonate as a base in DMF at 80° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][OH:5].C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH:3]([O:6][CH2:7][CH2:8][NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:4][O:5][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)NCCOC(CO)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOC(COS(C)(=O)=O)COS(C)(=O)=O
Temperature: -3 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
A 20-L 4-neck round-bottom flask was flushed with N2, then charged a solution of tert-butyl 2-(1,3-dihydroxypropan-2-yloxy)ethylcarbamate (418 g, 1.8 mol, 1.0 eq) in dichloromethane (9000 mL, 21.5 v) and N,N-diisopropylethylamine (574 g, 4.4 mol, 2.5 eq). This is followed by dropwise addition of methanesulfonyl chloride (509 g, 4.4 mol, 2.5 eq) with stirring at −6-0° C. over 1 hour. The resulting mixture was stirred for 4 h at −6˜4° C., then washed with water (3×4000 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/EtOAc (1:1) to give 740 g (101.0%) of 2-(2-(tert-butoxycarbonylamino)ethoxy)propane-1,3-diyl dimethanesulfonate as a yellow oil.
Reaction SMILES: Br[C:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]([CH3:21])[N:13]=3)[CH2:8][CH2:7]2)[O:4][N:3]=1.[CH3:22][CH:23]([CH3:26])[C:24]#[CH:25].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:22][CH:23]([CH3:26])[C:24]#[C:25][C:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]([CH3:21])[N:13]=3)[CH2:8][CH2:7]2)[O:4][N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(N2CCC3(CC2)CC(Br)=NO3)n1
Reactant: C#CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(N2CCC3(CC2)CC(C#CC(C)C)=NO3)n1
Temperature: 120 °C
Yield: 33.1 %

Procedure:
A mixture of Compound 19a (50 mg, 0.141 mmol), 3-methyl-1-butyne (48 mg, 0.705 mmol), sodium carbonate (74.6 mg, 0.704 mmol) and Cu (44.8 mg, 0.705 mmol) was heated in a sealed vessel at 120° C. for 32 h, adding every 8 h additional equal amounts of amounts of 3-methyl-1-butyne, sodium carbonate and Cu. Afterwards, the mixture was cooled, added with CH2Cl2, filtered on celite and evaporated to dryness in vacuo. The residue was purified by automated flash chromatography (SP1®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 75:25 then isocratic Petroleum Ether-EtOAc from 9:1 giving 16 mg of the title product. Yield: 33.1%.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)([O-:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:13]1[CH:14]=[CH:15][N:16]=[C:12]1[N+:9]([O-:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: ClCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1nccn1Cc1ccccc1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
Benzyl chloride (1.8 mL, 15.4 mmol, 1.2 equiv) was added to a solution of 2-nitroimidazole (1.45 g, 12.8 mmol) and triethylamine (3.6 mL, 25.7 mmol, 2 equiv) in DCM (40 mL). The reaction mixture was stirred at reflux for 72 h, allowed to cool to rt, diluted with DCM, washed with H2O and brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 7:3) to afford 1.31 g of the title compound as a white solid: ES-MS: 204.0 [M+H]+; tR=3.72 min (System 1); TLC: Rf=0.22 (Hex/EtOAc, 7:3).