Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH2:9])=[O:8])[N:5]=[C:4]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=1>COC(OC)(OC)CCCC>[CH2:3]([C:2]1[NH:1][C:2]2[N:6]([N:5]=[C:4]([C:10]3[O:11][CH:12]=[CH:13][CH:14]=3)[CH:3]=2)[C:7](=[O:8])[N:9]=1)[CH2:4][CH2:10][CH3:14]
Reactant: NC(=O)n1nc(-c2ccco2)cc1N
Agent: CCCCC(OC)(OC)OC
Product: CCCCc1nc(=O)n2nc(-c3ccco3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A mixture of 3.0 g of the product of Example 1 and 10 ml of trimethylorthovalerate is heated at 130 C. for 30 minutes. The reaction mixture is cooled to room temperature and diluted with hexanes. The resulting colorless solid is collected by filtration, washed with hexanes and dried to give 2.0 g of the desired product as a solid, m.p. 190° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl.ClCCl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([C:22]#[N:23])[CH:16]=[C:17]([NH2:19])[CH:18]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: N#Cc1cc(-c2nc(-c3ccc(F)cn3)no2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1cc(N)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Yield: 23.3 %

Procedure:
3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole (30 mg, 0.096 mmol) and tin(II) chloride dihydrate (109 mg, 0.48 mmol) in ethanol (1 mL) were sealed in a glass vial and then heated at 78 oC for 2 hours. The reaction was cooled and dichloromethane was added to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography of the residue using hexanes:ethyl acetate:dichloromethane 1:3:4 followed by recrystallization using methanol afforded 6.3 mg (23%) of 3-(5-fluoropyrid-2-yl)-5-(3-amino-5-cyanophenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.69 (d, 1H), 8.25 (m, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.61 (m, 1H), 7.11 (s, 1H), 4.17 (bs, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:16](=O)[CH3:17]>OS(O)(=O)=O>[CH3:16][CH:17]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH:2]([C:13]([OH:15])=[O:14])[NH:1]1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC=O
Agent: O=S(=O)(O)O
Product: CC1NC(C(=O)O)Cc2c1[nH]c1ccccc21
Yield: 69 %

Procedure:
L-tryptophan (5.10 g, 25 mmol), H2SO4 (0.01 M, 30 ml) and 40% acetaldehyde (9 ml) were added in a 250 ml round-bottom flask, and then stirred and reacted at room temperature for 8 h. After filtration, wash with water and drying, white solids (4.0 g, 69%) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].ClC1C=C(C=CC=1)C(OO)=[O:29].[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:9])=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)c1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1Br
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
391 mg of 5-{3-bromo-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone (Example 336) dissolved in 50 ml dichloromethane was stirred at 0° C. for 50 minutes in the presence of 183 mg of 70% m-chloroperoxybenzoic acid. Then 10 ml 5% aqueous sodium hydroxide was added to the reaction mixture and the mixed solution was stirred for another 10 minutes. The dichloromethane was removed in vacuo and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was then concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=1:1) to give 310 mg of 5-(3-bromo-4-(methylsulfinyl)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone. NMR: δ1.58 (s, 6H), 2.84 (s, 3H), 7.30 (m, 2H), 7.38 (m, 3H), 7.78 (dd, J=8.4, 1.8 Hz, 1H), 7.88 (d, J=5.4 Hz, 1H), 7.90 (d, J=2.7 Hz, 1H). IR (cm−1): 1698, 1619, 1388, 1064.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2]C.I[CH2:26]CC>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)([CH3:26])[CH3:2]
Reactant: CCCI
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Product: CC(C)Oc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3

Procedure:
Following the procedure for the preparation of 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and substituting 2-iodopropane for 1-iodopropane while making non-critical variations the title compound was obtained as 236 mg (56%) of a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.88 (br s, 1 H), 7.36-7.26 (m, 3 H), 7.16-7.12 (m, 1 H), 7.05-7.00 (m, 2 H), 6.95 (d, J=7.2 Hz, 1 H), 4.33-4.27 (m, 1 H), 3.11-3.03 (m, 2 H), 2.96-2.94 (m, 2 H), 2.87-2.81 (m, 2 H), 2.48-2.35 (m, 2 H), 1.15-1.08 (m, 6 H); HRMS (FAB) calcd for C21H24N2O+H1: 321.1967 found 321.1949.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=3[O:27][CH:28]([CH3:30])[CH3:29])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:34]([F:45])[CH:33]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([CH2:23][NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:34]([F:45])[CH:33]=4)=[CH:21][C:20]=3[O:27][CH:28]([CH3:30])[CH3:29])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)Oc1cc(C=O)ccc1Cn1nc(-c2ccccc2)cc1-c1ccccc1
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)c(OC(C)C)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of 4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]-3-isopropoxybenzaldehyde (0.38 g, 0.95 mmol) and ethyl 3-(4-amino-2-fluorophenyl)propanoate (0.20 g, 0.95 mmol) in 1,2-dichloroethane (7.0 mL) was added acetic acid (0.16 mL, 2.86 mmol) and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (0.61 g, 2.86 mmol) was added, and the mixture was further stirred for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/1) to give the title compound (0.52 g, yield 92%) as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[O:10][C:11]([C:14]2[C:15]([CH3:24])=[N:16][C:17]([O:22]C)=[C:18]([CH2:20][CH3:21])[CH:19]=2)=[N:12][N:13]=1)(C)(C)C.[I-].[Na+].Cl[Si](C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl.C(OCC)C.C(#N)C>[NH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[C:17](=[O:22])[NH:16][C:15]=2[CH3:24])=[N:12][N:13]=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]
Reactant: CCc1cc(-c2nnc(CNC(=O)OC(C)(C)C)o2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOCC
Product: CCc1cc(-c2nnc(CN)o2)c(C)[nH]c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of [5-(5-ethyl-6-methoxy-2-methyl-pyridin-3-yl)-[1,3,4]oxadiazol-2-ylmethyl]-carbamic acid tert-butyl ester (358 mg, 1.03 mmol) and sodium iodide (463 mg, 3.09 mmol) under a nitrogen atmosphere is added anhydrous acetonitrile (4 mL) followed by chlorotrimethylsilane (388 μL, 3.09 mmol). The reaction mixture is stirred at 50° C. under nitrogen for 8 hr. The black/dark brown reaction mixture is allowed to cool and then quenched with water (0.7 mL). After stirring for 20 min the mixture is evaporated. Isopropanol is added and the black suspension treated with triethylamine to give a yellow orange mixture. This crude suspension is purified by flash chromatography on a 2-gram silica gel cartridge by elution with dichloromethane:methanol (19:1 increasing to 9:1). The fractions containing the product are combined and evaporated to give an orange oil. This oil is treated with 10% trifluoroacetic acid in dichloromethane and a black mixture forms. Diethyl ether is added and the resulting suspension is filtered off to give 5-(5-aminomethyl-[1,3,4]oxadiazol-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one as its trifluoroacetic acid salt (196 mg, 55% yield) as a beige solid. LC/MS: RT: 2.10 min, m/e 235 (M+H); 1H NMR (300 MHz, d6-DMSO, δ, ppm): 12.19 (1H, s), 8.70 (3H, br.s), 7.66 (1H, s), 4.46 (2H, s), 2.58 (3H, s), 2.44 (2H, q), 1.12 (3H, t).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:25][C:26]([F:31])([F:30])[CH:27]1[O:29][CH2:28]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:23])([F:24])[CH:20]([F:21])[F:22])[CH:13]=2)[CH2:28][CH:27]([OH:29])[C:26]([F:31])([F:30])[F:25])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Reactant: FC(F)(F)C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 55 °C
Yield: 44.8 %

Procedure:
EX-528B) N-(3-nitrophenyl )-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine (3.25 g, 9.44 mmol) from EX-528A and 1,1,1-trifluoro-2,3-epoxypropane (0.895 mL, 10.4 mmol) were dissolved in 15 mL of acetonitrile. Ytterbium (III) trifluoromethane-sulfonate (0.77 g, 1.24 mmol) was added, and the stirred solution was warmed to 55° C. for 48 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10 to give 1.93 g (45%) of the desired 3-[(3-nitrophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a brown oil. HRMS calcd. for C18H16F7N2O4: 457.0998 [M+H]+, found: 457.1008. 1H NMR (CDCl3) δ3.7 (dd, 1H), 3.9 (dd, 1H), 4.4 (m, 1H), 4.8 (m, 2H), 5.9 (tt, 1H), 7.0-7.2 (m, 4H), 7.3-7.4 (m, 2H), 7.6 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:11])=[N:9][NH:10][C:6]=2[CH:5]=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH2:22][NH2:23]>C(O)CCC>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH2:22][NH:23][C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[NH:10][N:9]=[C:8]([CH3:11])[C:7]=12
Reactant: Cc1n[nH]c2cncc(Cl)c12
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCCCO
Product: COc1ccc(CNc2cncc3[nH]nc(C)c23)c(OC)c1
Yield: 42.3 %

Procedure:
A solution of 4-chloro-3-methyl-1H-pyrazolo[4,3-d]pyridine (330 mg, 1.9 mmol) and 1-(2,4-dimethoxyphenyl)methanamine (0.58 mL, 3.9 mmol) in 1-butanol was heated in the microwave at 150° C. for 40 minutes. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (240 mg, 42%). LCMS for C16H19N4O2 (M+H)+: m/z=299.1; Found: 299.2.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([O:15][C:16]1[CH:17]=[C:18]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[CH:19]=[CH:20][C:21]=1[CH3:22])[N:9]=2)=[O:4].C(N(CC)CC)C.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:22][C:21]1[CH:20]=[CH:19][C:18]([NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=2)=[CH:17][C:16]=1[O:15][C:10]1[N:9]=[C:8]2[S:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)=[N:14][C:13]2=[CH:12][CH:11]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)CCl)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)CN3CCN(C)CC3)sc2n1
Temperature: 60 °C
Reaction time: 14 h
Yield: 54.7 %

Procedure:
To a solution of N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-methylphenyl]-3-(trifluoromethyl)benzamide (218 mg, 0.419 mmol) in tetrahydrofuran (5 mL) were added triethylamine (117 μL, 0.838 mmol) and 1-methylpiperazine (93.4 μL, 0.838 mmol), and the mixture was stirred at 60° C. for 14 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel column chromatography (ethyl acetate/methanol=100/0→90/10), and precipitated with ethyl acetate to give the title compound (134 mg, 55%) as a white powder.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH:21]=O>>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][NH:10][C@H:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH2:8][OH:9]
Reactant: NC(CO)c1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Product: OC[C@H](NCc1ccc2ccccc2c1)c1ccccc1

Procedure:
Using 1.00 g (7.29 mmol) of (R)-phenylglycinol ((R)-VIII-2) and β-naphthoaldehyde, a similar operation was carried out to obtain (R)-N-(β-naphthyl)methyl-2-phenylglycinol (2.01 g) ((R)-II-3) quantitatively. ##STR318##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][O:11][CH2:12][CH2:13]O.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>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O.O>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([O:8][CH2:13][CH2:12][O:11][CH3:10])=[CH:6][N:7]=1
Reactant: Oc1cnc(Cl)c(F)c1
Reactant: COCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOc1cnc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 6-chloro-5-fluoro-pyridin-3-ol (CAS registry 870062-76-3) (800 mg, 5.42 mmol), 2-methoxy-ethanol (454 mg, 0.471 ml, 5.96 mmol) and triphenylphosphine (2.199 g, 8.13 mmol) in THF (40 ml) was added dropwise a solution of DIAD (1.731 g, 8.13 mmol) in THF (20 ml) while keeping the temperature at 0-5° C. The reaction mixture was stirred for 20 h at room temperature, water and brine were added and the mixture was diluted with EtOAc. The aqueous layer was twice extracted with EtOAc, the combined organic layers were dried over Na2SO4, filtered, the filtrate was concentrated and yielded after trituration with Et2O and filtration, the title compound as a white solid. The filtrate yielded another batch of the product after purification by prep. NP HPLC using an Alltech Grom Saphir 65 Si 10 μM 250×50 mm column (heptane/EtOAc, gradient 0-1.7 min 15% EtOAc, 1.7-17 min 15-100% EtOAc, 17-24.3 min 100% EtOAc, 24.3-27.8 min 0% EtOAc).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[NH2:16])=[N:8]1.F[C:18]1[C:23]([C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[CH:22][CH:21]=[CH:20][N:19]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[NH:16][C:18]2[C:23]([C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][N:28]4[CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:8]1
Reactant: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Reactant: Nc1cccc2nn(C3CCCCO3)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: c1cnc(Nc2cccc3nn(C4CCCCO4)cc23)c(-c2ncnc3c2ncn3C2CCCCO2)c1
Reaction time: 1 h
Yield: 42.9 %

Procedure:
A solution of 2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (37.4 mg, 172 μmol) and 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (51.5 mg, 172 μmol) in THF (1.0 mL) was cooled in an ice bath and treated dropwise with LHMDS (0.55 mL of a 1.0 M solution in THF, 3 equiv.). A deep red solution was obtained. The mixture was stirred for 60 min and then quenched with water (0.050 mL). The mixture was extracted with EtOAc from saturated aqueous NaHCO3, dried (MgSO4) and concentrated to give a dark residue. 2-(Tetrahydro-2H-pyran-2-yl)-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-2H-indazol-4-amine (36.6 mg, 42.8% yield) was obtained by flash chromatography on silica (50% EtOAc/hexane) (yellow band on column) as a yellow oil which crystallized upon standing. 1H NMR (400 MHz, CDCl3) δ 12.75 (br. s., 1H); 9.77 (d, J=7.82 Hz, 1H); 9.12 (s, 1H); 8.44 (d, J=3.52 Hz, 1H); 8.38 (s, 2H); 8.06 (d, J=7.04 Hz, 1H); 7.41 (d, 1H); 7.35 (d, J=7.63 Hz, 1H); 6.92-7.03 (m, 1H); 5.88 (d, 1H); 5.73 (d, 1H); 4.13-4.30 (m, 2H); 3.84 (br. s., 2H); 2.17-2.35 (m, 3H); 2.00-2.16 (m, 3H); 1.79 (br. s., 6H). m/z (API-ES) 497.1 (M+H)+.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]3[CH2:25][CH2:26][CH2:27][C:28]4[S:32][CH:31]=[CH:30][C:29]=4[C:20]3=[N:19]2)=[CH:14][CH:13]=1>O(Cl)Cl>[CH:9]([C:31]1[S:32][C:28]2[CH2:27][CH2:26][CH2:25][C:21]3[C:20](=[N:19][N:18]([C:15]4[CH:14]=[CH:13][C:12]([CH3:11])=[CH:17][CH:16]=4)[C:23](=[O:24])[CH:22]=3)[C:29]=2[CH:30]=1)=[O:10]
Reactant: Cc1ccc(-n2nc3c(cc2=O)CCCc2sccc2-3)cc1
Reactant: CN(C=O)c1ccccc1
Agent: ClOCl
Product: Cc1ccc(-n2nc3c(cc2=O)CCCc2sc(C=O)cc2-3)cc1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A mixture of 4.7 g of N-methylformanilide in 3.3 ml of phosphrus oxychloride was stirred at room temperature for an hour and 5.4 g of 2-(4-methylphenyl)-2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one was added thereto. After stirring at room temperature for 2 hours, the mixture was poured into ice-cold water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1) as an eluent. The solid was recrystallized from a mixed solvent of ethanol and ethyl acetate to give 3.5 g of 9-formyl-2-(4-methylphenyl)-2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one as a pale brown powder, melting at 127°-129° C.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@@H:14]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH2:13][O:12][C:11]1([CH3:22])[CH3:21])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([O:7][C:8]([N:10]1[C@@H:14]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:13][O:12][C:11]1([CH3:22])[CH3:21])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CCC(=O)O)COC1(C)C
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 100.2 %

Procedure:
Sodium hydroxide (27 mL of a 4.0 M solution in H2O, 108 mmol, 3.0 equiv.) was added to a solution of (4S)-4-(2-methoxycarbonylethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (prepared as described in Chida et al., J. Chem. Soc., Chem. Commun. 1992, 1064) (10.5 g, 36.5 mmol, 1 equiv.) in CH3OH (150 mL), and the resulting cloudy reaction mixture was stirred at 23° C. for 3.5 h. The mixture was concentrated under reduced pressure to 30 mL volume, and then was partitioned between 0.5 M HCl (150 mL) and EtOAc (2×150 mL). The combined organic layers were dried over MgSO4 and were gravity filtered. The filtrate was concentrated under reduced pressure and the residue dried under vacuum, to afford (4S)-4-(2′-carboxyethyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (10.0 g, 100% crude yield). This material was used without further purification: 1H NMR (CDCl3, mixture of rotamers) δ 1.49 (s), 1.57 (s), 1.60 (s), 1.84–2.05 (m), 2.39–2.41 (m), 3.71–3.74 (m), 3.91–4.05 (m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:23][C:24](O)=[O:25])([CH3:7])[CH3:6])[CH3:2].[Cl-].[NH4+].C(Cl)CCl.O.O[N:36]1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:27])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:23][C:24](=[O:25])[NH2:36])([CH3:7])[CH3:6])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1CC(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1CC(N)=O
Reaction time: 18 h
Yield: 86.4 %

Procedure:
2-(4-Benzyloxy-2-carboxymethyl-phenoxy)-2-methyl-propionic acid ethyl ester (500 mg, 1.34 mmol), ammonium chloride (108 mg, 2.02 mmol), EDC (3.86 mg, 2.01 mmol), and N-hydroxybenzotriazole hydrate (272 mg, 2.01 mmol) were combined in a flask and diluted with DMF (5 mL). Ethyl diisopropyl amine (0.70 mL, 4.0 mmol) was added. The solution was stirred for 18 h and partitioned between EtOAc (25 mL) and 1N HCl (10 mL). The organic layer was washed with saturated NaHCO3 solution (10 mL) then brine (10 mL), dried (Na2SO4), and concentrated. The crude product was purified by radial chromatography (hexanes/EtOAc 1/2 to 1/4) to give the title compound (430 mg, 86%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=1.[Br:11]N1C(=O)CCC1=O>CN(C)C=O>[Br:11][C:6]1[C:2]([OH:1])=[N:3][O:4][C:5]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)Cc1cc(O)no1
Solvent: CN(C)C=O
Product: O=C(O)Cc1onc(O)c1Br
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a solution of 6.0 g (35 mmoles) of 3-hydroxyisoxazol-5-ylacetic acid in 10 ml of N,N-dimethylformamide were added 6.5 g (42 mmoles) of N-bromosuccinimide, with ice-cooling and stirring. The mixture was stirred under ice-cooling for 2 hours and then at room temperature for 1 hour. The N,N-dimethylformamide was then distilled off under reduced pressure. The residue was dissolved in ethyl acetate and extracted with an aqueous solution of sodium hydrogen carbonate. The pH of the extract was adjusted to a value below 1.0 by the addition of concentrated hydrochloric acid, and then the solution was extracted with ethyl acetate. After drying the ethyl acetate extract, the solvent was distilled off. The crystals which formed the residue were recrystallized from a 1:5 by volume mixture of ethyl acetate and cyclohexane, giving 4.5 g (58%) of the title compound in the form of colourless plate crystals, melting point 167° C. with decomposition.