Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)[C:5]([NH2:20])=[C:4]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)[N:3]=1.[CH3:33][N:34]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)[CH3:35].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:33][N:34]([CH3:35])[C:36]1[CH:41]=[C:40]([C:2]2[N:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=3)[C:5]([NH2:20])=[C:4]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)[N:3]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: Nc1c(Oc2ccc(F)c(C(F)(F)F)c2)nc(Br)nc1Oc1ccc(F)c(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN(C)c1cccc(-c2nc(Oc3ccc(F)c(C(F)(F)F)c3)c(N)c(Oc3ccc(F)c(C(F)(F)F)c3)n2)c1
Temperature: 75 °C
Yield: 59.8 %

Procedure:
23 g of 2-Bromo-4,6-bis-(4-fluoro-3-trifluoromethyl-phenoxy)-pyrimidin-5-ylamine are dissolved under nitrogen together with 10.7 g of 3-(N,N-dimethylamino)phenylboronic acid, 0.4 g of tris(dibenzylideneacetone)dipalladium, 27.5 g of K3PO4 and 0.7 g of 2-dicyclohexyl-phosphino-2′,6′-dimethoxybiphenyl in 450 ml of toluene. The mixture is heated at 75° C. for 24 h, diluted with diethylether, washed with water and then dried over MgSO4. The solvents are removed under vacuum. 14.8 g of the title compound are isolated as white powder (mp. 110-111° C.) after purification by filtration and recrystallization from cyclohexane.
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[CH:6][NH:5][C:4]=2[CH:3]=[C:2]1[C:9]([O:11]C)=[O:10].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CO.C[O-].[Na+]>CO>[C:13]1([C:7]2[C:8]3[S:1][C:2]([C:9]([OH:11])=[O:10])=[CH:3][C:4]=3[NH:5][CH:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: COC(=O)c1cc2[nH]ccc2s1
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cc2[nH]cc(C3=CCCCC3)c2s1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a solution of methyl 4H-thieno[3,2-b]pyrrole-2-carboxylate (12 g, 68 mmol) and cyclohexanone (21 ml, 204 mmol) in methanol (300 ml) was added 28% sodium methoxide methanol solution (100 ml) and the mixture was stirred with heating under reflux for 2 days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 6N Hydrochloric acid (100 ml) was added and the precipitated solid was collected by filtration. The solid was washed successively with water (300 ml×5) and n-hexane (300 ml×3), and dried under reduced pressure to give 6-(cyclohex-1-enyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (17 g, yield 100%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)C.O.[NH2:15][NH2:16].C(OCC)C>C(O)C>[Cl:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[Cl:11])[C:4]([NH:15][NH2:16])=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: NNC(=O)c1ccc(Cl)c(Cl)c1
Yield: 57 %

Procedure:
17.5g (0.08 mol) of 3,4-dichlorobenzoic ethyl ester and 4.3g (0.086 mol) of 100%-hydrazine hydrate in 30 ml of ethanol were refluxed under heat for 6.5 hours. Upon cooled, the sedimented white crystals were added with ethyl ether and the reaction mixture was enough agitated and pulverized. The thus resulted products were filtered and enough washed with ethyl ether to provide 9.3g of 3,4-dichlorobenzoic hydrazide in white crystals. m.p.: 168°-170° C. Yield: 57%.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]([C:28](Cl)=[O:29])[CH2:23][CH2:22][C:21]2=[O:31]>C(N(CC)CC)C>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]([C:28]([N:8]1[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:29])[CH2:23][CH2:22][C:21]2=[O:31]
Reactant: CN1CCNC(CN2CCCC2)C1
Reactant: O=C1CCC(C(=O)Cl)c2ccc(Cl)cc21
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)C2CCC(=O)c3cc(Cl)ccc32)C(CN2CCCC2)C1
Yield: 111.1 %

Procedure:
The procedure described in Example 24 was repeated, but using 1.0 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 2.1 ml of triethylamine and 0.87 g of 6-chloro-1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride, to afford 0.92 g of the title compound, melting at 268°-274° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[N:6][CH:7]=1.C([Li])CCC.[O:28]1[CH2:31][C:30](=[O:32])[CH2:29]1.CO>C1COCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2[C:10]([CH2:9][O:8][C:5]3[N:6]=[CH:7][C:2]([C:30]4([OH:32])[CH2:31][O:28][CH2:29]4)=[CH:3][CH:4]=3)=[C:14]([CH3:15])[O:13][N:12]=2)=[CH:17][CH:18]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(Br)cn1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C2(O)COC2)cn1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A solution of 5-bromo-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine (110 mg, 0.3 mmol) in THF (3 mL) was treated at −78° C. with n-butyllithium (1.6 M solution in hexanes, 189 μL, 0.3 mmol) and then with 3-oxetanone (23.0 mg, 0.3 mmol). After 20 minutes methanol was added and the mixture was warmed to room temperature. Concentration and purification by chromatography (silicagel, heptane:ethyl acetate=85:15 to 8:3) to afforded the title product (32 mg, 30%) which was obtained as a colourless oil. MS: m/e=357.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[O:26]=[C:27]1[NH:31][C:30](=[O:32])[CH:29]([CH2:33][C:34]2[CH:44]=[CH:43][C:37]([O:38][CH2:39][C:40](O)=[O:41])=[CH:36][CH:35]=2)[S:28]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:26]=[C:27]1[NH:31][C:30](=[O:32])[CH:29]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:38][CH2:39][C:40]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:41])=[CH:43][CH:44]=2)[S:28]1
Reactant: COc1ccc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Yield: 93.5 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-methoxyphenoxy)phenyl]-N-methylcarbamate (2.0 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (2.0 g), diethyl cyanophosphonate (1.3 g), triethylamine (0.81 g) and anhydrous tetrahydrofuran (50 ml) and the reaction mixture was purified to give the desired product (3.3 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH:14]1[CH2:16][CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:4].CCN(CC)CC.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:14]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)[CH2:2][C:3]2=[O:4])[CH2:16][CH2:15]1
Reactant: COc1cccc(N(C(=O)CCl)C2CC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)N(C1CC1)C(=O)C2
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A mixture of 2-chloro-N-cyclopropyl-N-(3-methoxy-phenyl)-acetamide (1.25 g, 5.2 mmol), Pd(OAc)2 (0.06 g, 0.26 mmol), Et3N (0.79 g, 1.10 mL, 7.8 mmol), biphenyl-2-yl-di-tert-butyl-phosphane (0.155 g, 0.52 mmol) in toluene (6.0 mL) was stirred at 80° C. overnight. After cooling to room temperature the mixture was purified on silica gel (CH2Cl2/EtOAc, 9.5:0.5) to provide 1-cyclopropyl-6-methoxy-1,3-dihydro-indol-2-one as a solid (0.89 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[CH2:24]([N:26]([CH2:27][CH3:28])[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: CCNCC
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ncccc1C
Product: CCN(CC)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with diethylamine
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[NH2:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15].O.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:28][CH:29]([OH:32])[CH2:30]Br>[OH-].[Na+].C(O)C>[NH2:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[NH2:1][C@@H:2]1[C:7](=[O:9])[O:8][CH2:28][C:29]([OH:32])([CH3:30])[O:6][C:4](=[O:5])[CH2:3]1
Reactant: OC(CBr)CBr
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(O)COC(=O)[C@@H](N)CC(=O)O1
Reaction time: 8 h

Procedure:
8.5 g (0.064 mol) of L-aspartic acid and 9.4 g (0.0641 mol) L-glutamic acid is dissolved in 160 ml of water containing 10.2 g (0.255 mol) of sodium hydroxide. After dissolution, 6.8 g (0.064) sodium carbonate is added, followed by 80 ml ethanol. While refluxing the solution, 16.8 g (0.077 mol) 1,3-dibromo-2-propanol is added gradually during a period of 4 hours, followed by refluxing overnight. An additional 16.8 g (0.077 mol) of 1,3-dibromo-2-propanol is added, followed by all-day reflux. The solution is distilled to remove solvents and the resulting solid which contains HPAC and other materials is recovered and triturated with methanol/water. The purified solid is triturated again with methanol only and stirred overnight to remove residual materials, followed by dissolution in 10 cc water. Adjustment of the solution pH to 3-5 precipitates out HPAG. The final product is further purified by high pressure liquid chromotography.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:21][CH:20]([OH:22])[CH2:19]2)=[O:17])[CH:13]=[C:12]([C:23]([O:25]CC)=[O:24])[CH:11]=1)#[N:2].[OH-].[Na+].C(#N)C.Cl>O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:21][CH:20]([OH:22])[CH2:19]2)=[O:17])[CH:13]=[C:12]([C:23]([OH:25])=[O:24])[CH:11]=1)#[N:2]
Reactant: CCOC(=O)c1cc(C(=O)N2CC(O)C2)cc(-c2ccc(C)cc2C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CC(O)C3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round-bottom flask was charged with ethyl 2′-cyano-5-(3-hydroxyazetidine-1-carbonyl)-4′-methylbiphenyl-3-carboxylate (25 mg, 0.066 mmol), sodium hydroxide (10 mg, 0.25 mmol), acetonitrile (2 mL) and water (2 mL). The mixture was stirred at room temperature overnight. 1N aq. HCl (3 mL) was added and the volatiles were removed under reduced pressure. The residue was extracted with CH2Cl2, and the CH2Cl2 layer was concentrated to dryness to afford the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:11]=[C:12]=[O:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:24])[C:18]=2[CH:17]=[CH:16][N:15]=1.BrC1C=CC(CN=C=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:12]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH:17]=[CH:16][N:15]=[CH:14]3)=[O:13])([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)(N=C=O)c1ccc(Cl)cc1
Reactant: Nc1cccc2cnccc12
Agent: O=C=NCc1ccc(Br)cc1
Product: CC(C)(NC(=O)Nc1cccc2cnccc12)c1ccc(Cl)cc1

Procedure:
The title compound was prepared using the procedure described in Example 60F using 1-chloro-4-(1-isocyanato-1-methylethyl)benzene and 5-isoquinolinamine instead of the product from Example 60E and 1-bromo-4-(isocyanatomethyl)benzene. MS (ESI+) m/z 355 (M+H)+; MS (ESI−) m/z 353 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.63 (s, 6H), 7.23 (s, 1H), 7.37 (d, J 8.8, 2H), 7.47 (d, J 8.8, 2H), 7.73 (t, J 9.2, 1H), 7.93 (d, J 8.1, 1H), 8.25 (d, J 6.4, 1H), 8.39 (d, J 8.1, 1H), 8.67 (d, J 6.4, 1H), 8.87 (s, 1H), 9.58 (s, 1H); Anal. Calcd for C19H18ClN3O.HCl+0.25EtOH: C, 60.40; H, 5.33; N, 10.54. Found: C, 60.82; H, 5.23; N, 10.45.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:9]([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:21][C:22]#[N:23]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:9]([CH3:11])[CH3:10])=[C:6]([CH:7]=1)[O:8][CH2:21][C:22]#[N:23]
Reactant: N#CCI
Reactant: COc1cc(C(C)C)c(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c(OCC#N)cc1Cl
Temperature: 65 °C
Yield: 96.8 %

Procedure:
To a solution of 5-chloro-2-isopropyl-4-methoxy-phenol (10.36 g, 51.6 mmol) in 40 mL DMF was added K2CO3 (8.55 g, 62.0 mmol) and the mixture was heated to 65° C. After 15 minutes iodoacetonitrile (9.05 g, 54.2 mmol) was added and the mixture was heated to 80° C. for 1 hour. The mixture was cooled, poured into an ice/H2O mixture and extracted with 1:1 toluene/hexane. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by passing through a short plug of silica to afford (5-chloro-2-isopropyl-4-methoxy-phenoxy)-acetonitrile (11.97 g, 97%) as a white solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Li]CCCC.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Brc1cnc2ccccn12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2ccccn12
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 3-bromoimidazo[1,2-A]pyridine (0.10 g, 0.51 mmol) in THF (7.0 mL) under nitrogen atmosphere was cooled to −78° C. followed by dropwise addition of n-BuLi (1.30 M in hexane, 0.46 mL, 0.66 mmol). The resulting solution was stirred at same temperature for 45 min followed by addition of tributyltin chloride (0.14 mL, 0.53 mmol). The reaction mixture was then allowed to come to room temperature (45 min). After the completion of reaction (TLC monitoring), the reaction mixture was again cooled to −78° C. and quenched with dropwise addition of saturated NH4Cl solution. The reaction mixture was then extracted with EtOAc (2×25 ml). The combined organics was dried (Na2SO4), filtered and concentrated. The residue was used as such without further purification. MS: 409.10 (M+H)+.
Reaction SMILES: F[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[N+:8]([C:3]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccccn1
Reactant: O=[N+]([O-])c1ncccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncccc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-2-nitropyridine (3.32 g, 23.38 mmol) and 2-aminopyridine (2.0 g, 21.25 mmol) in DMF (35.4 mL) was added potassium tert-butoxide (4.77 g, 42.5 mmol). The solution was stirred under nitrogen at rt overnight. After 22 h, the mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). After drying with MgSO4, the solution was filtered and concentrated in vacuo to provide the crude material as a orange solid. The orange solid was purified by chromatography through a Redi-Sep™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide N-(2-nitropyridin-3-yl)pyridin-2-amine as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.53 (1H, s), 8.58 (1H, dd, J=8.4, 1.6 Hz), 8.15 (1H, dd, J=4.3, 1.4 Hz), 8.10-8.14 (1H, m), 7.66-7.76 (2H, m), 7.05 (1H, dt, J=8.4, 0.8 Hz), 6.93 (1H, ddd, J=7.2, 5.0, 0.9 Hz); LC-MS (ESI) m/z 217.0 [M+H]+.
Reaction SMILES: F[C:2]1[N:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[C@@H:14]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]2)[CH:9]=[N:8][CH:7]=1)=O.[NH2:33][NH2:34]>C1COCC1>[CH2:25]([C@@H:14]1[NH:15][CH2:16][CH2:17][N:12]([C:10]2[N:11]=[C:6]([C:4]3[C:3]4[C:2](=[N:32][CH:31]=[CH:30][CH:29]=4)[NH:34][N:33]=3)[CH:7]=[N:8][CH:9]=2)[CH2:13]1)[CH:26]([CH3:27])[CH3:28]
Reactant: NN
Reactant: CC(C)C[C@H]1CN(c2cncc(C(=O)c3cccnc3F)n2)CCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)C[C@H]1CN(c2cncc(-c3n[nH]c4ncccc34)n2)CCN1
Temperature: 75 °C

Procedure:
To a solution of (S)-tert-butyl 4-(6-(2-fluoronicotinoyl)pyrazin-2-yl)-2-isobutylpiperazine-1-carboxylate (160 mg, 0.3608 mmol) in THF (3 mL) was added hydrazine (1M in THF) (360.8 μL of 1 M, 0.3608 mmol) and the solution heated to 75° C. for 2 hrs. The reaction was allowed to cool and concentrated to give a yellow solid. This was columned on silica gel eluting with 1:1 EtOAc/hexanes to give (S)-3-(6-(3-isobutylpiperazin-1-yl)pyrazin-2-yl)-1H-pyrazolo[3,4-b]pyridine as a pale yellow solid. The Boc intermediate was dissolved in DCM (6 mL) and TFA (3 mL, 38.94 mmol) was added and the solution stirred at rt for 1 hr. Reaction was concentrated and partitioned between EtOAc and Sat. Na2CO3 and the organic washed with brine, dried (MgSO4) and concentrated to give a yellow solid. It was columned on silica gel eluting with 10% MeOH in DCM (1% NH4OH) to give (S)-3-(6-(3-isobutylpiperazin-1-yl)pyrazin-2-yl)-1H-pyrazolo[3,4-b]pyridine as an off white solid (52 mg, 42% 2 steps). ES+ 338. 1HNMR (DMSO) 0.92-0.94 (6H, dd), 1.24-1.35 (2H, m), 1.79-1.88 (1H, m), 2.56-2.61 (1H, m), 2.67-2.80 (2H, m), 2.92-3.05 (2H, m), 4.25 (1H, d), 4.33 (1H, d), 7.32 (1H, dd), 8.30 (1H, s), 8.57-8.61 (2H, m), 8.73 (1H, d), 14.14 (1H, brs).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[CH3:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:25])=[O:24])=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-methylsulfonylbenzenesulfonyl chloride as described in synthetic METHOD B to give a white solid (20.9 mg) with purity >90%. MS (pos) m/z 405.3.
Reaction SMILES: ClC1N=C2C(N=C(C3([F:16])COC3)N2C)=C(N2CCOC[C@@H]2C)N=1.[Cl:24][C:25]1[N:33]=[C:32]2[C:28]([N:29]=[C:30]([C:36]3(O)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:31]2[CH2:34][CH3:35])=[C:27]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][C@@H:44]2[CH3:49])[N:26]=1>>[Cl:24][C:25]1[N:33]=[C:32]2[C:28]([N:29]=[C:30]([C:36]3([F:16])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:31]2[CH2:34][CH3:35])=[C:27]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][C@@H:44]2[CH3:49])[N:26]=1
Reactant: CCn1c(C2(O)CCOCC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(F)COC1)n2C
Product: CCn1c(C2(F)CCOCC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21

Procedure:
This compound (h-1) was prepared in an analogous fashion to (S)-4-(2-chloro-8-(3-fluorooxetan-3-yl)-9-methyl-9H-pur-in-6-yl)-3-methylmorpholine, using (S)-4-(2-chloro-9-ethyl-6-(3-methylmorpholino)-9H-purin-8-yl)tetrahydro-2H-pyran-4-ol as the starting material. 1H NMR (CDCl3, 500 MHz) δ ppm 5.90 to 4.60 (broad s, 2H), 4.37 (q, J=7.1 Hz, 2H), 4.02 (dd, J=11.4 Hz, 3.4 Hz, 1H), 3.98 to 3.86 (m, 4H), 3.78 (dt, J=11.7 Hz, 7.1 Hz, 2H), 3.62 (td, J=11.9 Hz, 2.8 Hz, 1H), 3.48 (d, J=7.0 Hz, 1H), 2.55 to 2.35 (m, 2H), 2.22 to 2.06 (m, 2H), 1.43 (t, J=7.1 Hz, 3H), 1.40 (d, J=6.8 Hz, 3H); LC-MS m/z (method B2)=384 [M+H]+, RT=2.10 min.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:18])[CH2:4][P:5]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])(=[O:9])[O:6][CH2:7][CH3:8].[NH3:19]>C(O)C>[NH2:19][CH2:2][C@@H:3]([OH:18])[CH2:4][P:5]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOC(C)(OCC)P(=O)(C[C@H](O)CCl)OCC
Reactant: N
Solvent: CCO
Product: CCOC(C)(OCC)P(=O)(C[C@H](O)CN)OCC
Yield: 19 %

Procedure:
A solution of ethyl (2S)-(3-chloro-2-hydroxypropyl)(1,1-diethoxyethyl)phosphinate (5.0 g, 17 mmol) in ethanol containing 9% of ammonia was stirred in an autoclave at room temperature for 6 days and at 55° C. for one further day. The solution was evaporated and the residue was purified by chromatography on a wet-packed silica gel column eluting with methylene chloride/methanol (5-8% MeOH) containing 5% triethylamine. The appropriate fractions were combined, evaporated and diluted with methylene chloride and water. The aqueous layer was pH adjusted by the addition of a few mL of 10% aqueous Na2CO3 and repeatedly extracted with methylene chloride. The combined organic layers were dried over Na2SO4 and evaporated to give 0.9 g (19%) of ethyl (2R)-(3-amino-2-hydroxypropyl)(1,1-diethoxyethyl)phosphinate as a clear oil. Data: 1H NMR (500 MHz, CDCl3) δ 4.1-4.3 (m, 2H), 4.05 (b, 1H), 3.60-3.80 (m, 4H), 2.4-2.9 (m, 2H), 1.7-2.1 (m, 2H), 1.4-1.5 (dd,3H), 1.3-1.4 (m, 3H), 1.2 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][CH2:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:31])(C)(C)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:28](=[O:27])[CH2:29][C:30]([C:32]4[S:33][C:34]([Cl:37])=[CH:35][CH:36]=4)=[O:31])[CH:15]([CH2:19][CH2:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccc(Cl)s1
Reactant: CCCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Solvent: c1ccncc1
Product: CCCC1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)CC(=O)c1ccc(Cl)s1

Procedure:
The titled compound is prepared by a modification of a procedure published by Witzeman and Nottingham. (J. Org. Chem. 1991, 56, 1713.). 1-(4-Aminoquinazoline-7-ylmethyl)-3-propyl-piperazine-2-one (0.299 g, 1 mmol) and 3-(5-chloro-thiophen-2-yl)-3-oxo-propionic acid tert-butyl ester (0.287 g, 1.1 mmol) are dissolved in 10 ml of pyridine. The flask containing the resulting solution is placed in an oil bath preheated to 125° C. The reaction is heated with stirring under a stream of nitrogen gas for one hour until most of the pyridine had evaporated. The remaining pyridine is evaporated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% CH3OH/H2CCl2 to 10% CH3OH/H2CCl2 to provide the product (0.48 g, 0.98 mmol). The product could be recrystallized from CH2Cl2/hexane to yield a yellow solid. M.P. 120-5° C. (dec). MS (ion spray) m/z 486, (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[C:17]1([CH2:23][C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:24](=[O:25])[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C(O)Cc1ccccc1
Product: O=C(Cc1ccccc1)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 62 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and phenylacetic acid in 62% yield following procedure 1. The product was crystallized from methanol. 100% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=327, 1H NMR (MeOH-d4): 3.69 s (2H), 6.21 s (1H), 7.03 t, 7 Hz (1H), 7.12 t, 8 Hz (1H), 7.21–7.28 m (6H), 7.33–7.36 m (2H), 7.46 d, 8 Hz (1H), 7.54 dd, 7.1 Hz (1H), 7.89 d, 8 Hz (1H).