Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[C:11]([CH:15]=[CH:16][CH3:17])=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1)[CH3:2].C1C[O:21]CC1>[OH-].[Na+]>[CH2:1]([O:3][C:4]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH:16][CH3:17])[C:7]=1[C:8]([OH:21])=[O:10])=[O:9])[CH3:2]
Reactant: CC=Cc1cccc2nc(OCC)oc(=O)c12
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Product: CC=Cc1cccc(NC(=O)OCC)c1C(=O)O

Procedure:
Alternatively, the title compound was prepared by stirring a solution of 2-ethoxy-5-propenyl-4H-3,1-benzoxazin-4-one in THF (5 ml) and 2% sodium hydroxide (5 ml) for 6 hours. The organic solvent was removed by evaporation. The aqueous solution was acidified to pH=2 with dropwise addition of 6 M HCl. The solution was extracted with ethyl acetate and the organic was dried (magnesium sulphate) and evaporated to give an oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:2]1.CCN(CC)CC.[CH:18]([N:21]1[C:25]([C:26]2[N:35]=[C:34]3[N:28]([CH2:29][CH2:30][O:31][C:32]4[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][C:33]=43)[CH:27]=2)=[N:24][CH:23]=[N:22]1)([CH3:20])[CH3:19]>C(Cl)Cl>[CH:18]([N:21]1[C:25]([C:26]2[N:35]=[C:34]3[C:33]4[CH:36]=[C:37]([S:40]([N:1]5[CH2:4][CH:3]([N:5]6[CH2:10][CH2:9][O:8][CH2:7][CH2:6]6)[CH2:2]5)(=[O:42])=[O:41])[CH:38]=[CH:39][C:32]=4[O:31][CH2:30][CH2:29][N:28]3[CH:27]=2)=[N:24][CH:23]=[N:22]1)([CH3:20])[CH3:19]
Reactant: C1CN(C2CNC2)CCO1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CC(N4CCOCC4)C3)ccc1OCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-azetidin-3-ylmorpholine (52 mg, 0.36 mmol) and NEt3 (84 μL, 0.61 mmol) in DCM (5 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (100 mg, 0.12 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 16 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-6% 2M NH3/MeOH in DCM then C18, gradient 20-50% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 122 (40 mg, 65%). LCMS: RT 3.00 min [M+H]+ 500.3. 1H NMR (DMSO, 400 MHz): δ 8.87 (1H, d, J=2.40 Hz), 8.02 (1H, s), 7.94 (1H, d, J=0.62 Hz), 7.72 (1H, dd, J=8.62, 2.42 Hz), 7.32 (1H, d, J=8.62 Hz), 5.73-5.64 (1H, m), 4.64-4.63 (4H, m), 3.78 (2H, t, J=7.73 Hz), 3.58 (2H, dd, J=8.39, 5.80 Hz), 3.42 (4H, t, J=4.34 Hz), 3.03-3.01 (1H, m), 2.15-2.09 (4H, m), 1.49 (6H, d, J=6.62 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[Br:17]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([Br:17])=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(F)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Br)cc(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.5 %

Procedure:
To a mixture of 0.78 g of 2-amino-5-fluorobenzoic acid and 100 ml of N,N-dimethylformamide was added 1.1 g of N-bromosuccinimide at room temperature, and the mixture was stirred at room temperature for 5 hours. After water was added to the reaction mixture, a deposited precipitate was collected by filtration, and then washed with acetone to obtain 0.43 g of 2-amino-3-bromo-5-fluorobenzoic acid of the formula:
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH:35]=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([OH:6])=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC(COc2ccccc2C=O)C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(COc2ccccc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of sodium chlorite (1.37 g; 15.10 mmol; 5.5 eq.) and sodium dihydrogenphosphate (1.19 g; 9.89 mmol; 3.6 eq.) in water (8 mL) was added dropwise to a mixture of 2-methyl-2-butene (2.7 mL) and 3-(2-formyl-phenoxymethyl)-azetidine-1-carboxylic acid tert-butyl ester (800 mg; 2.75 mmol; 1 eq.) in 1,4-dioxane (8 mL) and the resulting mixture was stirred at room temperature for 1 hour. The 1,4-dioxane was evaporated in vacuo, water was added and the pH made acidic with 1M HCl. The precipitate was filtered off to afford the title compound (827 mg, 98%) as a white solid. HPLC (max plot) 100%; Rt 3.58 min. UPLC/MS: (MS−) 306.4 ([M−H]−).
Reaction SMILES: Br[Si](C)(C)C.[P:6]([O:12][C@H:13]1[CH2:17][O:16][C@@H:15]2[C@H:18]([O:21][N+:22]([O-:24])=[O:23])[CH2:19][O:20][C@H:14]12)([O:10]C)([O:8][CH3:9])=[O:7].CO>C(#N)C>[P:6]([OH:10])([O:12][C@H:13]1[CH2:17][O:16][C@@H:15]2[C@H:18]([O:21][N+:22]([O-:24])=[O:23])[CH2:19][O:20][C@H:14]12)([O:8][CH3:9])=[O:7]
Reactant: COP(=O)(OC)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O[N+](=O)[O-]
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: CO
Product: COP(=O)(O)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromotrimethylsilane (0.191 mL, 1.47 mmol) was added to a stirred room temperature mixture of dimethyl (3S,3aS,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl phosphate (400 mg, 1.34 mmol) in acetonitrile (6 mL) at 0° C., and the mixture was stirred at room temperature for 1 hour. Methanol (5 mL) was added, and the solution was concentrated. The residue was purified by preparative HPLC, eluting with 10-100% acetonitrile/water+0.1% trifluoroacetic acid, to afford the title compound as a white gum. 1H NMR (500 MHz, CD3OD) δ 5.45 (tt, J=5.3, 2.6 Hz, 1H), 5.00 (q, J=5.4 Hz, 1H), 4.74 (ddd, J=9.7, 7.2, 2.8 Hz, 1H), 4.57 (d, J=4.9 Hz, 1H), 4.09 (d, J=10.5 Hz, 1H), 3.97 (dt, J=11.3, 2.5 Hz, 1H), 3.92-3.83 (m, 2H), 3.72 (d, J=11.2 Hz, 3H); LC-MS: m/z 286.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[Se:4][NH:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([N:3]1[C:2]([CH3:14])([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[Se:4]1)(=[O:17])[CH3:16]
Reactant: CC1(C)N[Se]c2c([N+](=O)[O-])cccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1[Se]c2c([N+](=O)[O-])cccc2C1(C)C
Yield: 93 %

Procedure:
The 3,3-dimethyl-7-nitrobenzisoselenazoline described in Example 1 (130 mg, 0.5 mmol) is treated with 1 ml of acetic anhydride and 1 ml of pyridine at 60° C. for 1.5 hours. The mixture is then evaporated to dryness. The residue is triturated with a mixture of ethyl acetate and cyclohexane (1:2). The red solid is filtered and rinsed to provide the expected amide (140 mg, 93%).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN=C=NCCCN(C)C.[NH2:56][C@@H:57]([CH3:73])[CH2:58][N:59]1[CH:63]=[CH:62][C:61]([C:64]2[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[C:66]([Cl:72])[CH:65]=2)=[N:60]1>C(Cl)Cl>[C:1]([C:4]1[NH:5][N:6]=[C:7]([C:9]([NH:56][C@@H:57]([CH3:73])[CH2:58][N:59]2[CH:63]=[CH:62][C:61]([C:64]3[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[C:66]([Cl:72])[CH:65]=3)=[N:60]2)=[O:11])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
3-Acetyl-1H-pyrazole-5-carboxylic acid (10.20 g, 66.2 mmol), DCM (195 ml) and DIPEA (11.52 ml, 66.2 mmol) were placed in to the reaction flask under nitrogen atmosphere. HBTU (3.27 g, 8.63 mmol), EDCI (12.68 g, 66.2 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (15 g, 57.5 mmol) were added in this order and the mixture was stirred overnight at RT. The solvent was distilled close to dryness under vacuum, 2-propanol (25 ml) was added and the mixture was distilled to dryness. 2-Propanol (127 ml) was added, heated to reflux, water (23 ml) was added and the mixture was stirred for 15 min. The mixture was cooled to RT, stirred overnight and cooled to 5° C. The precipitate was filtered, washed with 2×10 ml of cold 2-propanol:water (70:30) and dried under vacuum to obtain 18.7 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 1.17 (d, 3H), 2.50 (s, 3H), 4.21-4.53 (m, 3H), 6.93 (d, 1H), 7.31 (s, 1H), 7.81 (d, 1H), 7.86-8.07 (m, 3H), 8.40-8.54 (bs, 1H), 14.14 (bs., 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13](=[O:23])[CH2:14][N:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl[CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1>C1COCC1>[CH3:11][O:12][C:13](=[O:23])[C:14]([N:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:30]=1)[CH2:25][C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1
Reactant: COC(=O)CN=Cc1ccccc1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N=Cc1ccccc1
Reaction time: 24 h

Procedure:
A solution of potassium bis(trimethylsilyl)amide (11.34 g, 54 mmol) in THF (100 ml) was added dropwise to a mixture of (benzylidene-amino)-acetic acid methyl ester (3.83 g, 21.63 mmol) and 4-chloromethyl-1-trityl-1H-imidazole (21.6 g, 60.18 mmol) in THF (200 ml) at −78° C. The resultant solution was warmed to ambient temperature and stirred for 24 hours. After removal of THF, the reaction mixture was subsequently partitioned between ethyl acetate and brine. The aqueous layer was washed two times with ethyl acetate. The ethyl acetate extracts were combined, dried over MgSO4, filtered and concentrated to give the crude title compound of 53A.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][CH:9]([S:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:23][CH2:22][CH2:21][N:20]4[CH:24]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=5)[N:26]=[C:19]4[C:18]=3[CH:33]=2)=[O:13])[CH2:8][CH2:7]1)([CH3:5])[CH2:3][OH:4].C(O)(C(F)(F)F)=[O:35].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:5][C:2]([N:6]1[CH2:7][CH2:8][CH:9]([S:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:23][CH2:22][CH2:21][N:20]4[CH:24]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=5)[N:26]=[C:19]4[C:18]=3[CH:33]=2)(=[O:35])=[O:13])[CH2:10][CH2:11]1)([CH3:1])[CH2:3][OH:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(CO)N1CCC(S(=O)c2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(CO)N1CCC(S(=O)(=O)c2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To an ice-cooled solution of 2-methyl-2-[4-(2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfinyl)piperidin-1-yl]propan-1-ol 197 (30 mg, 0.064 mmol) in DCM (2 mL) was added TFA (25 μL, 0.318 mmol) followed by a slow addition of a solution of m-CPBA (13 mg, 0.076 mmol) in DCM (0.5 mL) and the resulting mixture was stirred for 1 h at RT. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 5-30% MeOH in 0.5% TFA/H2O). To an ice-cooled solution in DCM (10 mL) of the product thus obtained was added TFA (12 μA) followed by a solution of m-CPBA (13 mg, 0.076 mmol) in DCM (0.5 mL). The mixture was stirred at RT for 1.5 h and then volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (C18, gradient 5-30% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. Further purification by column chromatography (Si-PCC, gradient 2-8% 2M NH3/MeOH in DCM) afforded 199 as a white solid (14 mg, 47%). LCMS: RT 2.03 min [M+H]+ 483.1. 1H NMR (DMSO, 400 MHz): δ 8.95 (1H, d, J=2.41 Hz), 8.53 (1H, ddd, J=4.81, 1.80, 0.93 Hz), 8.00-7.94 (2H, m), 7.85 (1H, td, J=7.69, 1.84 Hz), 7.68 (1H, dd, J=8.62, 2.43 Hz), 7.29-7.22 (2H, m), 4.65-4.55 (4H, m), 4.21 (1H, t, J=5.42 Hz), 3.22-3.10 (3H, m), 3.07-2.99 (2H, m), 2.09 (2H, bt, J=11.55 Hz), 1.86 (2H, bd, J=12.02 Hz), 1.50-1.37 (2H, m), 0.87 (6H, s)
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]1([C@H:13]([NH2:15])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>CCOC(C)=O>[C:7]1([C@H:13]([NH:15][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CN[C@H](C)c1ccccc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Methyl 2-bromoacetate (621 g, 4.1 mol) was added dropwise to a mixture of (1R)-1-phenylethanamine (410 g, 3.4 mol) and triethylamine (377 g, 3.7 mol) in EtOAc (4.5 L) at r.t. The mixture was then stirred at 50-60° C. overnight then cooled to r.t. The mixture was then washed with water (800 mL) and brine (100 mL), dried (Na2SO4) and concentrated in vacuo to give the title compound (587 g, 90%) as yellow oil; 1H NMR: (CDCl3) 1.29 (3H, d), 3.13-3.24 (2H, m), 3.60 (3H, s), 3.68-3.71 (1H, m), 7.13-7.26 (5H, m).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:11]([C:12]1[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=1)[C:10]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:9]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(NC2=CC(=O)CC2)cc1OC1CCCCC1
Product: COc1ccc(N(Cc2ccccc2)C2=CC(=O)CC2)cc1OC1CCCCC1
Yield: 89.4 %

Procedure:
According to the same procedure as in Example 26, using 3-(3-cyclohexyloxy-4-methoxyanilino)-2-cyclopenten-1-one produced in Example 13(3) instead of 3-(3-cyclopentyloxy-4-methoxyanilino)-2-cyclopenten-1-one, and using benzyl bromide instead of methyl iodide, the title compound (yield 89.4%) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.CC(N(C)C)=O.C1C(=O)N(Br)C(=O)C1.[CH3:44][C@H:45]1[O:50][C@@H:49]([CH3:51])[CH2:48][N:47]([C:52](=[S:54])[NH2:53])[CH2:46]1>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:54][C:52]([N:47]3[CH2:48][C@H:49]([CH3:51])[O:50][C@H:45]([CH3:44])[CH2:46]3)=[N:53][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Reactant: C[C@@H]1CN(C(N)=S)C[C@H](C)O1
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@@H]1CN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
To N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (1.5 g, 3.40 mmol) was added DMA (10 mL) and NBS (0.61 g, 3427 mmol). After stirring at rt for 10 min, (2R,6S)-2,6-dimethyl-4-morpholinecarbothioamide (0.800 g, 4.59 mmol) was added and stirring continued for 2 h. Water was added and the solid was collected by filtration and dried over two days to afford the title compound of Step A (1.80 g, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 7.49-7.63 (m, 3H), 7.45 (t, J=7.6 Hz, 1H), 7.39 (t, J=6.4 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 6.46 (d, J=5.3 Hz, 1H), 3.88 (d, J=11.4 Hz, 1H), 3.66 (br. s., 1H), 2.94 (s, 2H), 2.78 (s, 2H), 1.14 (d, J=6.0 Hz, 6H). m/z (ES+): 597 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>C(OCC)(=O)C>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[N:8][N:7]4[C:2]([NH:31][CH:28]5[CH2:30][CH2:29]5)=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccco3)nn12
Reactant: NC1CC1
Solvent: CCOC(C)=O
Product: c1coc(-c2nn3c(NC4CC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 100 °C
Yield: 32 %

Procedure:
4-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (100 mg, 0.26 mmol) and cyclopropylamine (5 mL) were put in a steel bomb. After heating at 100° C. for 3 days, the reaction was allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by purification with flash chromatography (3:7 ethyl acetate:hexanes) gave 3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine (34 mg, 32%) as a yellow foam. 1H NMR (CDCl3): δ 8.15 (d, 1H), 7.67 (d, 1H), 7.56 (d, 1H), 7.30 (t, 1H), 6.86 (d, 1H), 6.57 (d, 1H), 6.52 (m, 1H), 6.36 (d, 1H), 6.32 (s, 1H), 5.14 (d, 1H), 4.36 (m, 1H), 2.63 (m, 1H), 2.08 (m, 2H), 1.76–1.52 (m, 6H), 0.86 (m, 2H), 0.75 (m, 2H). MS m/401 (M+1).
Reaction SMILES: [CH3:1][C:2]([O:5][OH:6])([CH3:4])[CH3:3].[CH3:7][C:8]([CH3:10])=[O:9].[CH3:11]O>[Pd].[Pt]>[CH3:1][C:2]([O:5][OH:6])([CH3:4])[CH3:3].[CH3:7][C:8]([O:9][O:5][C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:11])[CH3:10]
Reactant: CO
Reactant: CC(C)=O
Agent: [Pd]
Agent: [Pt]
Agent: CC(C)(C)OO
Product: CC(C)(C)OOC(C)(C)C
Yield: 5 %

Procedure:
A 19.1% solution of TBHP in TBA decomposed over a commercial 0.15% Pd, 0.15% Pt on alumina gave (80° C., 0.5 space velocity) 74.2 TBHP conversion with selectivity to TBA of 84.1%, DTBP 5.0%, acetone 10.9%, and methanol 2.6%. Minor products including carboxylic acids were also formed.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7]1)=[O:5])C.C(O)C.[OH-].[Na+].[ClH:36]>ClCCl>[ClH:36].[C:25]1([N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCCCCCN(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCCCCCN(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The ester prepared in Example 3 (3.4 g, 8.3 mmol) was dissolved into ethanol (10 ml) and a 12 N sodium hydroxide solution (1.5 ml) was added. The reaction mixture was stirred at room temperature for 6 h. A concentrated hydrochloric acid solution (2.3 ml) was added with cooling of the reaction vessel in an ice-bath and dichloromethane (300 ml) was added. The resulting emulsion was dried over sodium sulphate and the solvent evaporated in vacuo to give a residue which was crystallised from ethyl acetate. This afforded 2.8 g (81% of the title compound.
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH:14]=[CH2:15])[CH3:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:28]1[CH:37]=[N:36][C:31]2=[N:32][CH:33]=[CH:34][N:35]=[C:30]2[CH:29]=1>O1CCCC1.C1C=CC=CC=1>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][CH2:15][C:28]1[CH:37]=[N:36][C:31]2=[N:32][CH:33]=[CH:34][N:35]=[C:30]2[CH:29]=1)[CH3:11]
Reactant: C=CC(OCC)OCC
Reactant: Brc1cnc2nccnc2c1
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCOC(CCc1cnc2nccnc2c1)OCC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 9-BBN (10.2 mL of a 0.5M solution in tetrahydrofuran) at 0° C. was added dropwise 0.77 mL of acrolein diethyl acetal and the mixture allowed to warm slowly to room temperature. After 15 hours, the mixture was diluted with 12 mL dry tetrahydrofuran followed by the sequential addition of potassium phosphate (1.6 g), palladium(1,1'-bis(diphenylphosphino)ferrocenyl) dichloride (160 mg) and 7-bromo-pyrido[2,3-b]pyrazine (924 mg) and then heated to reflux on an oil bath. After 5 hours, the mixture was cooled to 0° C., diluted with 15 mL benzene and the excess reagents quenched by the addition of 2N sodium hydroxide (3.5 mL) and 30% hydrogen peroxide (2.5 mL). The mixture then extracted with ethyl acetate, washed with brine and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane, 1:4; then 1:1; then 4:1) to give the title compound (1.2 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:18][CH3:19])[C:15](O)=[O:16].N1C=CC=CC=1>CCOCC>[CH3:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:18][CH3:19])[C:15]([Cl:3])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: CC=C(C(=O)O)c1ccccc1COC
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC=C(C(=O)Cl)c1ccccc1COC
Temperature: 20 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
At 0° to 5° C., 3.7 g of thionyl chloride was dripped into 4.9 g (24 mmol) of α-(2-methoxymethylphenyl)-β-methylacrylic acid and 2.5 g of pyridine in 40 ml of ether. The mixture was stirred for 3 hours at about 20° C. After filtration, the residue was washed with diethyl ether. The filtrate was combined with the ether phase. After removal of the solvent, there was obtained 5.2 g (96.5%) of the title compound as a colorless oil. The crude product can be used for further reactions without any additional purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:29])=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:12]([Cl:27])[C:11]2=[O:28])[CH:9]=1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32].C(N(CC)CC)C.[NH4+].[Cl-]>O1CCCC1>[Cl:27][C:12]1[C:11](=[O:28])[N:10]([C:8]2[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=2[F:29])[CH2:3][NH:2][C:30](=[O:33])[CH2:31][CH3:32])[C:15]([CH3:16])=[CH:14][C:13]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CN)ccc1F
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)NCc1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one hydrochloride (250 mg, 0.56 mmol), propionyl chloride (49 μL, 0.56 mmol), triethylamine (195 μL, 1.4 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C. for 5 min the reaction was completed by LC-MS. The reaction mixture was poured into a saturated aqueous NH4Cl solution. The aqueous mixture was extracted with ethyl acetate. The organic phase was dried with Na2SO4 and concentrated in vacuo to obtain (240 mg, 91%) as a yellow solid. 1H NMR (400 MHz, (CD3)2SO) δ 8.3 (t, J=5.8 Hz, 1H), 7.6 (q, J=8.7 and 6.58 Hz, 1H), 7.38 (d, J=7.78 Hz, 1H), 7.3 (dd, J=2.6 and 7.6 Hz, 1H), 7.22 (d, J=7.51 Hz, 1H), 7.12 (td, J=2.0 and 6.5 Hz, 1H), 6.65 (s, 1H), 5.3 (s, 2H), 4.23 (d, J=3.6 Hz, 2H), 2.1 (q, J=7.7 Hz 2H), 1.98 (s, 3H), 0.98 (t, J=7.5 Hz, 3H) ppm. ES-HRMS m/z 465.1203 (M+H calcd for C23H21ClF3N2O3 requires 465.1187).