Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH3:12])[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]3)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH3:12])[N:3]=[C:2]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]4)[C:10]=12
Reactant: Cn1nc(Br)c2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)OC(C)(C)C)c2c(N)ncnc21
Temperature: 120 °C
Yield: 70.9 %

Procedure:
To a 25 mL pressure tube was charged 3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (670 mg, 2.94 mmol), 1,1-dimethylethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate (1014 mg, 2.94 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (120 mg, 0.147 mmol), and sodium carbonate (494 mg, 5.88 mmol) followed by dioxane (8 mL), and water (2 mL). The reaction was heated at 120° C. for 40 minutes in a microwave reactor. LCMS showed no more SM. The reaction was cooled to room temperature, the mixture was transferred into a 100 mL Erlenmeyer flask, rinsed by EtOAc, with the water layer and black greasy solid stayed in tube (total 50 mL of EtOAc was added to the mixture). White solid was formed in brown solution. The solid was filtered to give titled product (764 mg).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH:26][CH2:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[OH:26][CH2:27][C:28]1[CH:33]=[C:32]([C:10]2[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]3[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:8]=3[N:9]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2c1cnn2C(C)C
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: C1COCCO1
Product: CCOC(=O)c1cc(-c2cccc(CO)c2)nc2c1cnn2C(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 1-isopropyl-6-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 g, 2.62 mmol), 3-(hydroxymethyl)phenyl boronic acid (0.438 g, 2.88 mmol) and Pd(PPh3)4 (0.303 g, 0.262 mmol) in 1,4-dioxane (15 mL) was purged with argon for 10 min. Then 2M Na2CO3 solution (4.5 mL, 9.4 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h and after completion of the reaction water was added to it. Extraction was carried out using EtOAc the combined organic layers were washed with water dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 0.81 g of target compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].CN(C)C=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.Cl.[CH2:44]([NH:46][C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[N:57]=[C:58]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][C@@H:67]3[CH3:72])[C:59]3[CH2:65][NH:64][CH2:63][CH2:62][C:60]=3[N:61]=2)=[CH:52][CH:51]=1)=[O:48])[CH3:45]>>[C:1]([CH2:3][C:4]([N:64]1[CH2:63][CH2:62][C:60]2[N:61]=[C:56]([C:53]3[CH:52]=[CH:51][C:50]([NH:49][C:47]([NH:46][CH2:44][CH3:45])=[O:48])=[CH:55][CH:54]=3)[N:57]=[C:58]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][C@@H:67]3[CH3:72])[C:59]=2[CH2:65]1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)CC#N)CC3)cc1
Temperature: 40 °C
Reaction time: 96 h

Procedure:
Cyanoacetic acid (0.0300 g, 0.000353 mol) in dry N,N-Dimethylformamide (1.60 mL, 0.0207 mol) was added 1-Hydroxybenzotriazole (0.0488 g, 0.000361 mol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0721 g, 0.000376 mol) then followed by N,N-Diisopropylethylamine (0.161 mL, 0.000924 mol) and then (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea hydrochloride (0.1000 g, 0.0002310 mol). The reaction mixture heated at 40° C. and was stirred for 4 days. The reaction mixture was concentrated, chromatographed through silica gel again (12 g, 0-10% MeOH in dichloromethane), and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.69 (s, 1H), 8.18 (d, J=8.8, 2H), 7.48 (d, J=8.8, 2H), 6.18 (t, J=5.6, 1H), 4.65 (d, J=15.7, 1H), 4.51-4.38 (m, 1H), 4.26-4.14 (m, 2H), 3.96-3.84 (m, 2H), 3.80-3.56 (m, 5H), 3.44 (dd, J=19.8, 12.6, 2H), 3.15-3.07 (m, 2H), 3.02-2.94 (m, 1H), 2.84 (s, 1H), 1.25 (t, J=5.4, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+464.2 (M+H)+.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH3:7][C:8]1[CH:18]=[CH:17][C:11](OCC(O)=O)=[CH:10][CH:9]=1>CN(C)C=O.ClCCl>[CH3:7][C:8]1[CH:18]=[CH:17][C:11]([O:3][CH2:2][C:1]([Cl:6])=[O:5])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(OCC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(OCC(=O)Cl)cc1
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (8.83 ml) and N,N-dimethylformamide (3 drops) were added at room temperature to a solution of 4-methylphenoxyacetic acid (6.73 g) in dichloromethane (70 ml), and the reaction mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, then the resulting acidic gas was removed as the toluene azeotrope, and the product was dried under reduced pressure to give 4-methylphenoxyacetyl chloride. A 1.61N solution of n-butyl lithium in hexane (25.2 ml) was added dropwise at −78° C. to a solution of (S)-4-benzyl-2-oxazolidinone (7.08 g) in tetrahydrofuran (70-ml), and after the completion of the dropwise addition, the reaction mixture was stirred at −78° C. for 30 minutes. To this resulting solution was added at −78° C. a solution of 4-methylphenoxyacetyl chloride obtained above in tetrahydrofuran (70 ml) followed by stirring at 0° C. for 1 hour. The resulting reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed successively with a 1N aqueous solution of hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (eluant; hexane/ethyl acetate =3/1˜1/1) to afford the target compound (9.00 g) as a colorless oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33]C(=O)C)=[CH:29][CH:28]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[OH:33][C:30]1[CH:29]=[CH:28][C:27]([CH:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:20])=[CH:32][CH:31]=1
Reactant: CC(=O)Oc1ccc(C(c2ccc(OC(C)=O)cc2)c2ccccc2NC(=O)C2CCCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(Nc1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1)C1CCCCC1
Yield: 57.5 %

Procedure:
To 2.21 g of Compound 101 obtained by Example 101 was added 50 ml of ethanol and 50 ml of saturated aqueous sodium hydrogencarbonate, and the mixture was heated under reflux for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. Precipitated crystals were washed with water and then recrystallized to afford 1.05 g of the desired compound (Compound 120)
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(Cl)C2N(C(C(O)=O)=CN=2)N=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1.ClC1C=C(Cl)C2N(C(C(NC3C=CN=CC=3)=O)=CN=2)N=1>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:48][C:45]3[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=3)=[O:14])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)c1cnc2c(Br)cc(Cl)nn12
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Nc1ccncc1)c1cnc2c(Cl)cc(Cl)nn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccncc1)c1cnc2c(Br)cc(Cl)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a 2 dram vial was added a mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid and 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylic acid (250 mg, 1.077 mmol), and oxalyl chloride (1.077 mL, 2.155 mmol) in dichloromethane (2 mL). The solution was stirred at 25° C. for 1 hour. The solvent and excess oxalyl chloride were removed in vacuo. The residue was dissolved in dichloromethane (2 mL), and triethylamine (0.451 mL, 3.23 mmol), pyridin-4-amine (152 mg, 1.616 mmol), and 2 crystals of DMAP were added. The reaction solution was stirred at 25° C. for 6 hours. The solution was quenched with dichloromethane, washed 2× with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a mixture of 6,8-dichloro-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (202 mg, 0.656 mmol, 60.8% yield). LC/MS, m/z 307.93 (M+1). HPLC Rt, 1.49 min. Waters Sunfire C18 column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35].[H-].[Na+].O>CN(C)C=O>[F:28][C:3]1[CH:4]=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CC(C)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 71.2 %

Procedure:
853 mg (2.19mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-1-benzopyran-4-one obtained in Example 66 was dissolved in 20 mL of dimethylformamide under argon atmosphere, 788 mg (4.38 mmol) of 1-bromo-5-methylhexane and 266 mg (6.65mmol) of sodium hydride (60% oil dispersion) were added under ice-cooling and the mixture was stirred at room temperature for 5.5 hours. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform: n-hexane=3:1) to give 762 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(5-methylhexylamino)-4H-1-benzopyran-4-one (yield: 71%).
Reaction SMILES: S1C2C=CC=CC=2N=C1N([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])C(C1C=CC=C2C=1CN(C1SC(Br)=C(C(OCC)=O)N=1)CC2)=O.[S:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N:44]=[C:43]1[NH:51][C:52]([C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[C:63]=1[CH2:62][N:61]([C:64]1[S:65][C:66]([CH:70]=[O:71])=[C:67]([Cl:69])[N:68]=1)[CH2:60][CH2:59]2)=[O:53]>>[Cl:69][C:67]1[N:68]=[C:64]([N:61]2[CH2:60][CH2:59][C:58]3[C:63](=[C:54]([C:52](/[N:51]=[C:43]4/[S:42][C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=5[N:44]/4[CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:53])[CH:55]=[CH:56][CH:57]=3)[CH2:62]2)[S:65][C:66]=1[CH:70]=[O:71]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1Br
Reactant: O=Cc1sc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)nc1Cl
Product: C[Si](C)(C)CCOCn1/c(=N\C(=O)c2cccc3c2CN(c2nc(Cl)c(C=O)s2)CC3)sc2ccccc21

Procedure:
Compound 45B was prepared in a similar manner to the synthesis of compound 34C by substituting compound 34B with compound 45A in step 3 of Example 34. Compound 45B was isolated as a white solid by trituration of the mixture of two isomers with 1:4 hexanes:EtOAc. The other isomer was isolated from the mother liquor: 1H NMR (DMSO-d6): δ 9.71 (s, 1H), 8.24 (d, J=7.82 Hz, 1H), 7.92 (d, J=7.58 Hz, 1H), 7.70 (d, J=8.06 Hz, 1H), 7.53-7.56 (m, 1H), 7.36-7.46 (m, 3H), 6.01 (s, 2H), 5.35 (s, 2H), 3.85 (t, J=5.92 Hz, 2H), 3.72-3.75 (m, 2H), 3.11 (t, J=6.04 Hz, 2H). MS (ESI(+)): m/z 585 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:3]=1[N:4]([CH2:9]Cl)[C:5](=[O:8])[CH2:6][Cl:7].[CH3:16][O:17][CH2:18][CH:19]([CH3:21])[OH:20]>C(Cl)CCl>[CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:3]=1[N:4]([CH2:9][O:20][CH:19]([CH3:21])[CH2:18][O:17][CH3:16])[C:5](=[O:8])[CH2:6][Cl:7]
Reactant: Cc1cccc(C)c1N(CCl)C(=O)CCl
Reactant: COCC(C)O
Solvent: ClCCCl
Product: COCC(C)OCN(C(=O)CCl)c1c(C)cccc1C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
About 12.3 g (0.050 mole) of 2',6'-dimethyl-N-(chloromethyl) 2-chloroacetanilide dissolved in twenty (20) ml of ethylene dichloride was added to 22.5 g (0.25 mole) of 2-methoxy-1-methyl ethanol. The solution was allowed to stand one hour at room temperature. Excess alcohol and HCl was removed under vacuum on a rotary evaporator. The residual oil was treated with an additional 22.5 g fresh alcohol for 30 minutes at 60° C. Excess alcohol and HCl was removed as before at 65° C./1 mm Hg. The light yellow oily residue weighed 14.86 g (99.1% yield). Refractive index of the oil, n26D 1.5263. Proton NMR was consistent with structure.
Reaction SMILES: CN(C)S([N:6]1[C:10]([CH2:11][NH:12][CH2:13][CH3:14])=[CH:9][N:8]=[CH:7]1)(=O)=O.[Cl:16][C:17]1[CH:22]=[C:21](F)[CH:20]=[CH:19][N:18]=1.Cl.N>C(O)C>[Cl:16][C:17]1[CH:22]=[C:21]([N:12]([CH2:13][CH3:14])[CH2:11][C:10]2[NH:6][CH:7]=[N:8][CH:9]=2)[CH:20]=[CH:19][N:18]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: CCNCc1cncn1S(=O)(=O)N(C)C
Agent: Cl
Agent: N
Solvent: CCO
Product: CCN(Cc1cnc[nH]1)c1ccnc(Cl)c1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A mixture of 5-ethylaminomethyl-imidazole-1-sulfonic acid dimethylamide (0.2 g, 0.86 mmol) and 2-chloro-4-fluoropyridine (0.12 g; 0.91 mmol) was heated in a sealed vessel in a microwave oven for 30 min at 140° C. Then after cooling a solution of hydrochloric acid in ethanol (5 N, 1 ml) was added and the mixture was stirred at 90° C. overnight. For workup aqueous ammonia solution was added to basic pH and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (SiO2; ethyl acetate/methanol 8:2) to yield a white solid, (0.13 g, 64%); MS (ISP): 239.0 ((M+H)+.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=O)[C:10]=2[C:16]#[N:17])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:20])=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:20][C:11]1[N:12]=[CH:13][CH:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]=1[C:16]#[N:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc[nH]c(=O)c2C#N)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccnc(Cl)c2C#N)cc1
Temperature: 110 °C
Yield: 88.8 %

Procedure:
A mixture of 4-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (1.00 g, 4.42 mmol) and phosphoryl trichloride (8 mL, 87 mmol) was heated to 110° C. for 15 h. The mixture was diluted with ethyl acetate (100 mL), carefully treated with saturated sodium bicarbonate (100 mL), neutralized to pH˜7 with careful addition of solid potassium carbonate while stirring vigorously, and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine (40 mL), dried (MgSO4) and concentrated to give 2-chloro-4-(4-methoxyphenyl)nicotinonitrile as a brown solid (960 mg, 89% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.54 (1H, δ, J=5.27 Hz), 7.48-7.82 (2H, m), 7.38 (1H, δ, J=5.27 Hz), 6.94-7.18 (2H, m), 3.90 (3H, s); MS (ES+) m/z: 245 (M+H); LC retention time: 3.303 min (analytical HPLC Method A).
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:35])[CH2:6][S:7][CH2:8][C@@H:9]1[CH2:13][C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][N:10]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N>N1C=CC=CC=1>[NH2:1][CH2:4][CH:5]([OH:35])[CH2:6][S:7][CH2:8][C@@H:9]1[CH2:13][C@@H:12]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[CH2:11][N:10]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC(O)CN=[N+]=[N-])N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC(O)CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-2-[(3-azido-2-hydroxypropyl)thiomethyl]-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.94 g) in pyridine (6 ml) was added triphenylphosphine (1.55 g) and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added conc. ammonia (0.50 ml) and the mixture was allowed to stand overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure. The resulting mixture was dissolved in ethyl acetate (40 ml) and the solution was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give (2S,4R)-2-[(3-amino-2-hydroxypropyl)thiomethyl]-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine. The residue containing the compound obtained above was dissolved in a mixture of ethyl acetate and water (3:1 V/V, 40 ml). To the solution was dropwise added a solution of 4-nitrobenzyloxycarbonyl chloride (0.87 g) in tetrahydrofuran (3 ml) with stirring at 2°-5° C., keeping the pH between 9-10 with 1N sodium hydroxide. The mixture was stirred at the same temperature for 1 hour. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (9:1 v/v). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-{3-(4-nitrobenzyloxycarbonyl)amino-2-hydroxypropyl}thiomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.25 g).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH:38]3[CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]3)[CH:37]=2)O1>>[NH:40]1[CH2:41][CH:38]([N:36]2[CH:37]=[C:33]([C:2]3[CH:24]=[CH:23][C:5]4[C:6]5[N:7]=[C:8]([C:14]6[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=6)[S:9][C:10]=5[CH2:11][CH2:12][O:13][C:4]=4[CH:3]=3)[CH:34]=[N:35]2)[CH2:39]1
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(C5CNC5)c4)ccc2-3)n(C(C)C)n1

Procedure:
Similarly to as described in General Procedure C, 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate. Removal of the tertbutoxycarbonyl protecting group was accomplished with trifluoroacetic acid in dichloromethane. Purification of the crude reaction mixture by reverse phase HPLC gave 406. LCMS: 448.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:17].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(N(CC)CC)C>[CH2:19]([N:18]([CH2:16][CH3:17])[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:15])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1cnoc1-c1cccc(Cl)c1
Reactant: CCNCc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Product: CCN(Cc1ccccc1)C(=O)c1cnoc1-c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-(3-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and N-ethylbenzylamine (8.1 mg, 0.060 mmol) as described in synthetic method A (using 21 μL of triethylamine and 45 μL of 1-propanephosphonic acid cyclic anhydride) and thereafter purified by preparative HPLC method B (without the extraction step) to give a solid (4.1 mg). MS (pos) m/z 341.2 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N+:10]([O-:13])=[C:9]([CH3:14])[C:8]=1[CH3:15].Cl[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>O1CCCC1>[CH3:14][C:9]1[C:8]([CH3:15])=[C:7]([O:6][CH2:5][CH2:4][O:3][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=[CH:11][N+:10]=1[O-:13]
Reactant: Cc1c(OCCO)cc[n+]([O-])c1C
Reactant: ClCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(OCCOCc2ccccn2)cc[n+]([O-])c1C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
0.39 g of 60% sodium hydride was added to a suspension of 1.20 g (6.5 mmol) of 4-(2-hydroxyethoxy)-2,3-dimethylpyridine N-oxide in 40 ml of tetrahydrofuran under cooling with ice in a nitrogen atmosphere to obtain a mixture. This mixture was stirred for 0.5 hour, followed by the addition of 0.83 g (6.5 mmol) of 2-chloromethylpyridine. The obtained mixture was heated under reflux for 8 hours, cooled and filtered. The filtrate was concentrated and purified by silica gel column chromatography (solvent: ethyl acetate/n-hexane=4:1~CHCl3 /MeOH=19:1) to obtain 0.61 g of 2,3-dimethyl-4-(2-pyridylmethoxyethoxy)pyridine N-oxide.