Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][C:52]1[C:53](=[O:62])[NH:54][C:55]([CH3:61])=[CH:56][C:57]=1[CH2:58][O:59][CH3:60].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:50][CH2:51][C:52]2[C:53](=[O:62])[NH:54][C:55]([CH3:61])=[CH:56][C:57]=2[CH2:58][O:59][CH3:60])=[O:16])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:12])[CH3:13])[C:6]=2[N:7]=1
Reactant: COCc1cc(C)[nH]c(=O)c1CN
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)nc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: O
Product: COCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
To a solution of 6-bromo-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.155 g, 0.549 mmol) in DMSO (2 mL), PyBOP (0.429 g, 0.823 mmol) was added and reaction stirred at room temperature for 15 min. Then 3-(aminomethyl)-4-(methoxymethyl)-6-methylpyridin-2(1H)-one (0.1 g, 0.549 mmol) was added and reaction stirred overnight. On completion, water was added and solid that precipitates out was filtered and washed with water to obtain the desired intermediate (0.06 g, 24.5%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[OH-].[K+].CN(C)C=O.[Cl:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=1>CCO>[Cl:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:22][CH:21]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
In 20 ml of EtOH, 9.4 g (6.4×10-2 mole) of phthalimide and 4.2 g of KOH were stirred for 30 minutes, followed by addition of 100 ml of DMF (dimethylformamide) and 5.2 g (2.5×10-2 mole) of 6-chloro-3-pyridylmethyl chloride. The mixture was stirred at 60° C. for 1 hour. The EtOH and DMF were distilled off under reduced pressure and the residue was chromatographed on a silica gel column and eluted with CH2Cl2. The above procedure gave 6.7 g of the title compound as colorless needles.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:23])=[O:12])[N:3]=1.[C:24]([O-:27])([O-])=[O:25].[K+].[K+]>O1CCOCC1.O.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>[Cl:23][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([F:22])([F:21])[F:20])[C:13]=1[C:11]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:24](=[O:25])[O:27][CH2:2]3)=[N:3]1)=[O:12]
Reactant: O=C(c1c(Cl)cccc1C(F)(F)F)n1nc(Br)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1OCc2cc(-c3nn(C(=O)c4c(Cl)cccc4C(F)(F)F)c4ccccc34)ccc21
Temperature: 100 °C

Procedure:
(0.97 g, 2.48 mmol), (3-bromo-1H-indazol-1-yl)(2-chloro-6-(trifluoro methyl)phenyl)methanone (1.0 g, 2.48 mmol), K2CO3 (1.03 g, 7.44 mmol) and Pd(PPh3)4 (0.143 g, 0.12 mmol) were suspended in 1,4-dioxane (15 mL) and H2O (3 mL). The reaction mixture was heated at 100° C. in a microwave reactor for 2 h. The reaction mixture was cooled to rt and diluted with H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (PE:EA=4:1) to afford the title compound as a pale yellow oil. LCMS (ESI) calc'd for C23H13ClF3N2O3 [M+H]+: 457. found: 457.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]1)([C:8]1C=CC=CC=1)[C:2]1C=CC=CC=1.CC(C)=O.[ClH:24]>[OH-].[OH-].[Pd+2].CC(O)C>[ClH:24].[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]1)([CH3:8])[CH3:2]
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(C)N1CC(CO)C1

Procedure:
A mixture of (1-benzhydrylazetidin-3-yl)methanol (4.0 g, 15.8 mmol), acetone (20 ml), 2-propanol (80 ml), c.HCl (1.5 ml) and Pd(OH)2 was hydrogenated at 50 psi/50° for 18 hours. The reaction mixture was filtered through Arbocel® and concentrated in vacuo, the residue was triturated with diisopropyl ether (50 ml) to give the title compound as a pale green hygroscopic powder (2.6 g, 99%). LRMS ESI+m/z 130 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](O)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: OCC1(c2ccc(Br)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
To a solution of 1-(4-bromophenyl)cyclobutanecarboxylic acid (300 mg, 1.20 mmol) in 1,4-dioxane (5 mL) was added borane dimethylsulfide complex (0.24 mL, 2.4 mmol) dropwise at 0° C. The ice bath was removed, and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was quenched with methanol (20 mL). The organic solvents were removed under reduced pressure to give a residue, which was dissolved in ethyl acetate, then washed with brine. The organic phase was concentrated to give [1-(4-bromophenyl)cyclobutyl]methanol (170 mg, 62% yield) as a yellow oil which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2([OH:28])[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)=[C:14]3[C:13](=[O:27])[O:12]2)[N:4]=1.[H-].[Na+:30]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([C:15]2[N:16]=[CH:17][CH:18]=[C:19]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:14]=2[C:13]([O-:27])=[O:12])=[O:28])[N:4]=1.[Na+:30]
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(-c4ccc(Cl)cc4)ccnc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(OC)nc(C(=O)c2nccc(-c3ccc(Cl)cc3)c2C(=O)[O-])n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.2 %

Procedure:
0.4 g of 7-(4,6-dimethoxypyrimidin-2-yl)-4-(4-chlorophenyl)-7-hydroxyfuro[3,4-b]pyridin-5-(7H)one was dissolved in 100 m of toluene, and 0.05 g of 60% sodium hydride was added thereto. The mixture was stirred at room temperature for one day. The precipitated crystals were collected by filtration and sufficiently washed with acetone to obtain 0.25 g (yield 60%) of the desired compound. m.p.: 263°-267° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([O:15][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:13][NH2:14])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24]([CH3:28])([CH3:27])[CH:25]=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([O:15][Si:16]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:21][CH3:22])[CH2:13][NH:14][CH2:23][C:24]([CH3:28])([CH3:27])[CH3:25])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cnc2ccccc12
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(CNCC(C)(C)C)c1c(Cl)cnc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a yellow clear solution of 2-(3-chloroquinolin-4-yl)-2-((triethylsilyl)oxy)ethanamine (A275-6) (0.217 g, 0.644 mmol) in DCM (2.15 mL) was added trimethylacetaldehyde (0.077 mL, 0.71 mmol), AcOH (0.045 mL, 0.77 mmol), and NaBH(OAc)3 (0.205 g, 0.966 mmol). The yellow homogeneous mixture was stirred at room temperature. After 2 h, the mixture was quenched with water (20 mL) and neutralized with 0.5 M NaOH (10 mL) to pH ˜9.0. The reaction mixture was extracted with DCM (2×50 mL). The organic extract washed with saturated NaCl (1×50 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow syrup. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 20% EtOAc in hexane, and dried under high vacuum to give N-(2-(3-chloroquinolin-4-yl)-2-((triethylsilyl)oxy)ethyl)-2,2-dimethylpropan-1-amine (A275) as colorless syrup. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (1H, s), 8.75 (1H, d, J=7.2 Hz), 8.04 (1H, dd, J=8.4, 1.0 Hz), 7.77 (1H, ddd, J=8.4, 6.9, 1.4 Hz), 7.61-7.68 (1H, m), 5.70 (1H, dd, J=7.7, 5.0 Hz), 3.26 (1H, dd, J=12.6, 8.1 Hz), 2.85 (1H, dd, J=12.6, 5.0 Hz), 2.23-2.39 (2H, m), 1.72 (1H, br. s.), 0.81 (9H, s), 0.72-0.79 (9H, m), 0.36-0.56 (6H, m); LCMS (ESI) m/z 407.1 (M+H)+.
Reaction SMILES: ClC1C=C(C=C(OC2C=C(O)C=CC=2Cl)C=1)C#N.C([O-])([O-])=O.[Cs+].[Cs+].BrCC1C2C(=NC(F)=CC=2)N(C(OC(C)(C)C)=O)N=1.[Cl:44][C:45]1[CH:46]=[C:47]([CH:50]=[C:51]([O:53][C:54]2[CH:59]=[C:58]([O:60][CH2:61][C:62]3[C:70]4[C:65](=[N:66][C:67]([F:71])=[CH:68][CH:69]=4)[N:64](C(OC(C)(C)C)=O)[N:63]=3)[CH:57]=[CH:56][C:55]=2[Cl:79])[CH:52]=1)[C:48]#[N:49]>C(O)(C(F)(F)F)=O>[Cl:44][C:45]1[CH:46]=[C:47]([CH:50]=[C:51]([O:53][C:54]2[CH:59]=[C:58]([O:60][CH2:61][C:62]3[C:70]4[C:65](=[N:66][C:67]([F:71])=[CH:68][CH:69]=4)[NH:64][N:63]=3)[CH:57]=[CH:56][C:55]=2[Cl:79])[CH:52]=1)[C:48]#[N:49]
Reactant: CC(C)(C)OC(=O)n1nc(COc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c2ccc(F)nc21
Agent: CC(C)(C)OC(=O)n1nc(CBr)c2ccc(F)nc21
Agent: N#Cc1cc(Cl)cc(Oc2cc(O)ccc2Cl)c1
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2cc(OCc3n[nH]c4nc(F)ccc34)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a manner identical to that described above for the synthesis of 1-2, from 2.97 g (10.68 mmol) of 3-chloro-5-(2-chloro-5-hydroxyphenoxy)benzonitrile (C-3), 3.29 g (10.15 mmol) of Cs2CO3, and 3.34 g (10.15 mmol) of tert-butyl 3-(bromomethyl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (37-5) was prepared crude 3-chloro-5-{2-chloro-5-[(1-t-butyloxycarbonyl-6-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]phenoxy}benzonitrile (37-6) as an oil. This BOC-protected material (3.66 g) was immediately dissolved in 10 mL TFA, and the resulting solution stirred for 20 minutes at room temperature. The crude reaction mixture was concentrated in vacuo and purified via silica gel chromatography (10-70% EtOAc/hexane) to yield the title compound. H1 NMR (CDCl3): 5.47 (s, 2H), 6.85 (d, 1H), 6.95 (d, 1H), 7.02 (s, 1H), 7.10 (s, 1H), 7.30 (s, 1H), 7.40 (d, 1H), 8.38 (t, 1H), 11.38 (bs, 1H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH2:17][C@@H:18]([C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[O:21])[N:19]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[O:21])[N:19]=2)=[CH:13][CH:14]=1
Reactant: COc1cc(C(=O)[C@@H]2CSC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)=N2)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2csc(-c3ccc(O)cc3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
At 0° C., to a solution of 58a (0.2 mmol) in 5 mL CH2Cl2 was added a solution of tetrabutylammonium fluoride in THF (1 N, 0.6 mmol) and stirred at RT for around 14 h until reaction was finished by TLC monitor. 67.0% yield. 1H NMR (500 MHz, DMSO-d6) δ 10.1 (s, 1H), 8.51 (s, 1H), 7.85 (d, 2H, J=8.50 Hz), 7.62 (s, 2H), 6.91 (d, 2H, J=8.5 Hz), 3.86 (s, 6H), 3.79 (s, 3H). MS (ESI) m/z 394.1 (M+Na)+, 369.9 (M−H)−.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15](OS(C(F)(F)F)(=O)=O)[C:14]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][NH2:44])=[O:40])([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([NH:44][CH2:43][CH2:42][NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[C:14]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1NCCNC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 45.1 %

Procedure:
A solution of methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-(trifluoromethanesulphonyloxy)benzoate (Intermediate 123, 0.05 g), N-(t-butoxycarbonyl)ethylenediamine (0.048 g), palladium acetate (0.006 g), cesium carbonate (0.065 g) and (+/−)BINAP (0.034 g) in toluene (1.5 ml) was stirred and heated at 100° C., under nitrogen for 20 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-35%, to give methyl 6-(benzenesulphonylmethyl)-2-[2-(t-butoxycarbonylamino)ethylamino]-3-(furan-3-yl)benzoate (0.023 g) as a yellow gum.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:13]1
Reactant: CCOC(=O)CC#N
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1NC(=O)c2ccccc2S1

Procedure:
Methyl thiosalicylate (6 g, 35.7 mM) and ethyl cyanoacetate (4 g, 35.4 mM) were dissolved in toluene (10 ml), and then triethylamine (5 ml, 35.8 mM) was added thereto. After heating under reflux for 7 hours, the reaction solution was concentrated. Ethanol was added to the residues and kept still, and the precipitated crystals were collected by filtration to give crude crystals. The product was recrystallized from ethanol to give the title compound as needle crystals (5.4 g, 60.7%).
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[N:24][OH:25])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.N1C=CC=CC=1>O1CCCC1.O.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[C:15]([N:16]2[N+:24]([O-:25])=[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]3=[N:17]2)=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(NNC3CCCCC3=NO)cc21
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: C#CCN1C(=O)COc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc21
Temperature: 80 °C

Procedure:
To a solution of 2-[2-(7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-on-6-yl)hydrazino]cyclohexanone oxime (0.4 g) in tetrahydrofuran (6 ml), 15% aqueous pyridine (7 g) was added, and a solution of copper sulfate (0.7 g) in water (1.5 ml) was added thereto, followed by heating at 80° C. for 2 hours. The reaction mixture was allowed to cool, combined with water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous copper sulfate solution, dried and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate as an eluent to give Compound No. 1 (0.2 g). m.p., 186°-187° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Se](=O)=[O:14]>>[CH3:1][C:2]1[C:11]([CH:12]=[O:14])=[N:10][C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: Cc1nc2ccccc2nc1C
Reactant: O=[Se]=O
Product: Cc1nc2ccccc2nc1C=O
Yield: 66 %

Procedure:
The title compound was prepared from 2,3-dimethylquinoxaline (6c) and selenium dioxide using methods as described in the literature for similar compounds (Kepez et al., 1989) in 66% yield.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:33][CH2:32][C:29]2([O:31][CH2:30]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[CH2:33][CH2:32][C:29]([CH2:30][F:1])([OH:31])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CF)CC1
Yield: 19.9 %

Procedure:
Tetrabutylammonium fluoride (1.0 M in THF, 5.6 ml, 5.6 mmol) was added to a solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (400 mg, 1.87 mmol) in tetrahydrofuran (5 ml), and the mixture was heated under reflux for 36 hours. The reaction solution was cooled and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 4-fluoromethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (87 mg, 19%).
Reaction SMILES: N([O-])=O.[Na+].NC1NC=NC=1/C=C/C1C=CC(C#N)=CC=1.[CH3:21][O:22][CH2:23][N:24]=[C:25]=[O:26].[N+:27](=[C:29]1[C:33](/[CH:34]=[CH:35]/[C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=2)=[N:32][CH:31]=[N:30]1)=[N-:28]>O.[H+].[B-](F)(F)(F)F.CS(C)=O>[CH3:21][O:22][CH2:23][N:24]1[C:25](=[O:26])[N:30]2[CH:31]=[N:32][C:33](/[CH:34]=[CH:35]/[C:36]3[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=3)=[C:29]2[N:27]=[N:28]1
Reactant: COCN=C=O
Reactant: N#Cc1ccc(/C=C/C2=NC=NC2=[N+]=[N-])cc1
Agent: F[B-](F)(F)F
Agent: N#Cc1ccc(/C=C/c2nc[nH]c2N)cc1
Agent: O=N[O-]
Solvent: CS(C)=O
Solvent: O
Product: COCn1nnc2c(/C=C/c3ccc(C#N)cc3)ncn2c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.8 %

Procedure:
Sodium nitrite (40 mg, 0.57 mmol) in water (0.5 mL) was added to a suspension of (E)-4-(2-(5-amino-1H-imidazol-4-yl)vinyl)benzonitrile (100 mg, 0.47 mmol) in 50% HBF4 (2 mL) at 0° C. After stirring at 0° C. for 20 minutes, the precipitate was filtered from solution and dried over P2O5. This diazo compound was used without further purification. Methoxymethyl isocyanate (150 mg, 1.8 mmol) was added to a solution of (E)-4-(2-(4-diazo-4H-imidazol-5-yl)vinyl)benzonitrile (80 mg, 0.36 mmol) in dry DMSO (1 mL) under nitrogen. The resulting solution was stirred at room temperature for 24 hours, then purified by column chromatography (5% MeCN/DCM) to give the title compound as a yellow solid (42 mg, 38%). δH (DMSO-d6) 8.48 (1H, s), 7.81 (1H, d, J=16.0), 7.71 (4H, m), 7.60 (1H, d, J=16.0) 5.72 (2H, s), 3.58 (3H, s); IR (cm−1) 2222 (C≡N), 1631 (C═N); MS (m/z) 309.1121 (C15H13N6O2 (M+1)) requires 309.1100.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:18])[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([NH2:51])[C:45]([NH2:50])=[CH:46][C:47]=1[O:48][CH3:49].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)CCl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:12][CH2:13][CH2:14][C:15](=[O:17])[NH:50][C:45]1[CH:46]=[C:47]([O:48][CH3:49])[C:42]([O:41][CH3:40])=[CH:43][C:44]=1[NH2:51])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(N)c(N)cc1OC
Reactant: CN(CCCC(=O)O)C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(N)c(NC(=O)CCCN(C)C(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.95 g 4-(benzyloxycarbonyl-methyl-amino)-butyric acid in 20 mL THF were added 3.3 mL of DIPEA, 0.61 g of HOBt and 0.86 g EDC. After stirring for 5 min 1.0 g of 4,5-dimethoxy-benzene-1,2-diamine dihydrochloride was added and the mixture was stirred at rt overnight. Saturated aq. NaHCO3 solution was added, the phases were separated and the organic phase was washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])[CH:10]=[CH:9][C:8]=2[NH2:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[K+].[C:26]([C:28]1[N:29]=[C:30]([C:41]([O-])=[O:42])[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=1)#[N:27].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:16])=[O:17])[CH:10]=[CH:9][C:8]=2[NH:24][C:41]([C:30]2[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[C:28]([C:26]#[N:27])[N:29]=2)=[O:42])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.7 %

Procedure:
A solution of 132 mg (0.377 mmol) of 2-cyclohex-1-enyl-4-[2-(mopholine-4-sulfonyl)-ethyl]-phenylamine (as prepared in the previous step) in CH2Cl2 (15 mL) was treated with 126 mg (0.414 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 93.9 mg (0.565 mmol) of PyBroP to form a slurry, which was treated with 197 μL (1.13 mmol) of DIEA. The mixture was stirred at RT for 3.5 h, diluted with CH2Cl2 (15 mL), and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 221 mg (98%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C29H41N5O5SSi, 600.3 (M+H). found 599.8.
Reaction SMILES: [Na].[CH3:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[Li+].[I-].[CH3:16][OH:17]>>[CH3:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][O:17][CH3:16]
Reactant: CO
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Agent: [I-]
Agent: [Li+]
Agent: [Na]
Product: COCc1cccc([N+](=O)[O-])c1C
Yield: 92 %

Procedure:
To a solution of sodium (0.10 g, 4.3 mmol) in methanol (40 ml) was added 2-methyl-3-nitrobenzylchloride (0.50 g, 2.7 mmol) and catalytic amounts of LiI under nitrogen. After the reaction occurred at 40° C. over night, the solvent evaporated and the residue was purified by chromatography (heptane/EtOAc) to give the title compound 450 mg, (92%) as a yellow oil.
Reaction SMILES: Cl.NO.C([N:7](C(C)C)CC)(C)C.C(O)C.[Cl:16][C:17]1[N:22]=[C:21]([NH:23][C:24]([NH:26]C(OCC)=O)=S)[C:20]([O:32][CH3:33])=[CH:19][CH:18]=1>O>[NH2:7][C:24]1[N:23]=[C:21]2[C:20]([O:32][CH3:33])=[CH:19][CH:18]=[C:17]([Cl:16])[N:22]2[N:26]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1nc(Cl)ccc1OC
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: COc1ccc(Cl)n2nc(N)nc12
Yield: 58.6 %

Procedure:
Hydroxylamine hydrochloride (9.6 g, 138 mmol) and diisopropylethylamine (14.4 mL, 10.7 g, 83 mmol) were mixed with ethanol (300 mL) for a few minutes and then N-(6-chloro-3-methoxy-2-pyridinyl)-N'-carboethoxythiourea (7.6 g, 27.5 mmol) was added with stirring. The resulting mixture was stirred at room temperature for 20 min and then heated to reflux for 3 hours. The volatile components were removed by evaporation and the residue obtained was mixed with water. The resulting slurry was filtered and the solids collected were washed with ether, a small amount of methanol, and finally hexane and were then dried. The title compound (3.2 g) was obtained as a tan powder melting at 207°-208° C.