Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:13][C@H:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[CH2:15]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[F:26][C:27]1[CH:28]=[C:29]([N:42]2[CH2:46][C@H:45]([CH2:47][N:48]3[CH:52]=[CH:51][N:50]=[N:49]3)[O:44][C:43]2=[O:53])[CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C1(P([Pd-4](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)C=CC=CC=1>[O:1]([CH2:13][C@H:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:32]3[CH:31]=[CH:30][C:29]([N:42]4[CH2:46][C@H:45]([CH2:47][N:48]5[CH:52]=[CH:51][N:50]=[N:49]5)[O:44][C:43]4=[O:53])=[CH:28][C:27]=3[F:26])=[CH:21][N:20]=2)[CH2:15]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: OC[C@H]1O[C@@H](OC[C@@H]2CC(c3ccc(Br)cn3)=NO2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC1(C)OB(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)C3)nc2)c(F)c1
Temperature: 70 °C
Yield: 38.4 %

Procedure:
[(5S)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methyl β-D-glucopyranoside (Intermediate 20, 0.150 g, 0.36 mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 7, 0.153 g, 0.39 mmol), sodium carbonate (0.152 g, 1.43 mmol), and tetrakis(triphenylphosphino)palladium(0) (0.041 g, 0.036 mmol) were mixed in DMF/water (10:1, 5 mL) under nitrogen and heated at 70° C. bath temperature for 4 hours. The solvent was evaporated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol 5:1 followed by crystallization from ethanol gave the product as colourless solid (83 mg). MS (ESP): 601.06 (MH+) for C27H29FN6O9
Reaction SMILES: O=[C:2]1[CH:7]([C:8](OCC)=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.Cl.[CH:21]([NH2:23])=[NH:22].CC[O-].[Na+]>CCO>[OH:9][C:8]1[C:7]2[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3][C:2]=2[N:22]=[CH:21][N:23]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: N=CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(O)ncnc2C1
Yield: 53.5 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (2.00 g, 7.39 mmol) in EtOH (37 mL) was added formamidine hydrochloride (910 mg, 11.08 mmol) followed by NaOEt (6.89 mL, 2.68 M in EtOH) dropwise. The mixture was then heated to reflux overnight. The mixture was concentrated in vacuo and then dissolved in a minimum amount of water. The pH was adjusted to pH 7 with 1 N HCl. The aqueous layer was then saturated with solid NaCl and extracted with a combination of EtOAc and DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 eluting with IPA/EtOAc afforded the desired product as a white solid (993 mg, 53%). MS (ESI) mass calcd. C12H12N3O3, 251.13. m/z found 252.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.05 (s, 1H), 4.42 (s, 2H), 3.69-3.61 (m, 2H), 2.63 (s, 2H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][CH2:12]O)=[C:9]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[NH:8][C:5]2=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:40]C(Br)(Br)Br>C1COCC1>[Br:40][CH2:12][CH2:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:8][C:9]=1[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16]
Reactant: BrC(Br)(Br)Br
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCBr
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
3-(2-bromoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine was prepared according to method D Step III with 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol (2.0 g; 6.43 mmol) in THF (30 mL) and triphenyl phosphine (2.56 g; 9.65 mmol) and perbromomethane (3.27 g, 9.65 mmol) in THF (40 mL) pre-stirred for 30 minutes. The crude mixture was purified by flash chromatography on silica gel (eluent 5 to 40% of ethyl acetate in heptanes) to yield 1.08 g (45%) of 3-(2-bromoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[N:14]=[C:15]=[O:16]>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:15]([NH:14][C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)=[O:16]
Reactant: O=C=Nc1cccs1
Reactant: CN1CC(=O)N=C1N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1cccs1
Temperature: 55 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To 9.4 g (83 mM) of creatinine in 100 ml of anhydrous DMF was added with stirring of solution of 9.2 g (75 mM) 2-thienyl isocyanate in 60 ml of toluene. After the addition was completed, the mixture was stirred at 55° C. for 1 hr., cooled, and the solvents removed in vacuo. The residue was recrystallized first from ethanol and then ethyl acetate (treated with charcoal) to give 5.3 g of the above urea as an off-white solid, m.p. 191°-192° C. (dec.).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[OH-].[Na+].CC1(C)[O:32][CH:31]([CH:33]2[O:35][CH2:34]2)[CH2:30][O:29]1>O.O1CCOCC1>[OH:35][CH:33]([CH:31]([OH:32])[CH2:30][OH:29])[CH2:34][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: CC1(C)OCC(C2CO2)O1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)C(O)CO)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10.0 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (DO3A) is dissolved in 40 ml of water, and the pH is set at 13 with 5N sodium hydroxide solution. A solution of 6.24 g (43.30 mmol) of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethylene oxide (DE 3,150,917) in 10 ml of dioxane is added thereto, and the mixture is stirred for 24 hours at room temperature. The mixture is diluted with 60 ml of water and extracted three times with 50 ml of ether. The aqueous phase is brought to pH 2 with 10% strength hydrochloric acid and evaporated. The residue is dissolved in a small amount of water and passed to a cation exchange column (IR 120). After flushing with water, the ligand is eluted with 0.5-normal aqueous ammonia solution. The fractions are evaporated, the ammonium salt is taken up in a small amount of water and passed over an anion exchange column (IRA 67). The mixture is first washed with water and then eluted with 0.5-normal aqueous formic acid. The product is evaporated under vacuum, the residue is dissolved in a small amount of hot methanol, and acetone is added, thus crystallizing the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][C:27](=[CH:29][O:30][CH3:31])[CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCC([O-])(C)C.[Na+].C(OC1C=C(C2[N:54]=C(C3CC(=O)C3)N3C=CN=C(Cl)C=23)C=CC=1)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][C:27](=[CH:29][O:30][CH3:31])[CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:54])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Reactant: COC=C1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC=C1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn23)C1
Temperature: 70 °C

Procedure:
1-(3-Benzyloxy-phenyl)-8-chloro-3-(3-methoxymethylene-cyclobutyl)-imidazo[1,5-a]pyrazine: To a solution of Ph3PCH2OMeCl (2.6 g, 7.44 mmol) in benzene (37 mL) a solution of sodium tert-amylate (819.0 mg, 7.44 mmol) in benzene (9.0 mL) was added at rt. The dark red solution was allowed to stir at rt for 10 min. at which point a solution of 3-[1-(3-Benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanone in benzene (30.0 mL) was added dropwise at rt. The reaction mixture was then heated to 70° C. for 4 h. The reaction was then quenched with NH4Cl sat. Aq. and extracted with diethyl ether (3×). The organic layers were washed with H2O (1×), brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. Purification via HPFC using a 50 g Jones silica gel column (30% EtOAc:Hex) to yield the desired product as a light yellow solid; 1H NMR (CDCl3, 400 MHz) δ 3.29-3.33 (m, 4H), 3.59 (s, 3H), 3.90 (q, 1H, J=8.2 Hz), 5.14 (s, 2H), 5.93 (s, 1H), 7.26-7.66 (m, 11H); MS (ES) 432.05 (M+1), 434.01 (M+3), 435.02 (M+4).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:13][NH2:14])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:15]([N:22]=[C:23]=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C(N(CC)CC)C>[CH2:15]([NH:22][C:23]([NH:14][CH2:13][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([C:9]([F:12])([F:10])[F:11])=[CH:6][N:5]=1)=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: S=C=NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)c1cnc(CNC(=S)NCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (0.12 g) and benzylisothiocyanate (0.11 g) in dry tetrahydrofuran (10 ml) was added triethylamine (10 drops) and the mixture stirred at room temperature for 12 hours. The solvent was evaporated and ethyl acetate added. The mixture was washed with 2M hydrochloric acid and then with saturated sodium bicarbonate solution. The organic layer was separated and the solvent removed to give the title product. 1H N.M.R. δ(ppm) 4.7 (2H, broad s), 4.95 (2H, d), 6.9 (1H, broad s), 7.3-7.55 (6H, m), 7.95 (1H, s) and 8.58 (1H, s).
Reaction SMILES: [CH3:1][P:2](=[O:7])([CH:5]=[CH2:6])[CH:3]=[CH2:4].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.O>[CH2:8]([N:15]1[CH2:6][CH2:5][P:2](=[O:7])([CH3:1])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: C=CP(C)(=O)C=C
Solvent: O
Solvent: C1CCOC1
Product: CP1(=O)CCN(Cc2ccccc2)CC1
Yield: 70.3 %

Procedure:
A solution of methyl divinyl phosphine oxide (1.16 g, 10.0 mmol) and benzylamine (1.20 mL, 11.0 mmol) in 1:1 THF/water (25 mL) was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford 1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide as a white solid (1.57 g, 70% yield).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[Cl:5][CH:6]1[C:12]2=[N:13][C:14]([CH3:22])=[C:15]([C:17](OCC)=[O:18])[CH:16]=[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7]1>CC(O)C>[Cl:5][CH:6]1[C:12]2=[N:13][C:14]([CH3:22])=[C:15]([C:17]([NH:3][C:2]([NH2:4])=[NH:1])=[O:18])[CH:16]=[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cc2c(nc1C)C(Cl)CCCC2
Solvent: CC(C)O
Product: Cc1nc2c(cc1C(=O)NC(=N)N)CCCCC2Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.7 %

Procedure:
In an atmosphere of argon, guanidine hydrochloride (4.08 g, 42.7 mmol) was added to 28% sodium methoxide methanol solution (8.0 ml, 41.5 mmol) at 0° C. After 30 minutes of stirring at the same temperature, the thus precipitated sodium chloride was removed by filtration using a glass filter and the resulting filtrate was evaporated under reduced pressure to obtain free guanidine. Guanidine and ethyl 9-chloro-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (1.10 g, 4.12 mmol) were suspended in 2-propanol (6.0 ml) and stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was mixed with water and extracted with ethyl acetate. The thus obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=10:1-5:1) to obtain the title compound (494.0 mg, 42.7%) as white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[OH2:12]>CC(C)=O>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([CH2:3][C:2]([OH:12])=[O:1])=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: O
Solvent: CC(C)=O
Product: N#Cc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(2-hydroxyethyl)benzonitrile (120 mg, 0.816 mmol) in acetone (3 mL), Jone's reagent (1.5 mL, 4.005 mmol) was added. After stirring for 10 minutes at room temperature, the crude reaction mixture was poured into water (10 mL) and extracted with CHCl3 (6×10 mL). Combined organics were dried over magnesium sulfate, filtered, and concentrated to give (4-cyanophenyl)acetic acid which was used without purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH:46](Br)[CH3:47]>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:46]([CH3:47])[CH2:45][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(Br)CBr
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CC(C)c1ccccc1N1/C(=N\N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SCC1C
Temperature: 85 °C

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (300 mg, 0.572 mmol) and potassium carbonate (316 mg, 2.29 mmol) in butanone (4 ml) was added 1,2-dibromopropane (0.072 ml, 0.686 mmol). The reaction was heated to 85° C. overnight. The reaction was determined to be complete by LCMS. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided a yellow solid. The solid was recrystallized from MeOH. The solid was filtered, washed with MeOH, and dried to provide the title compound as a yellow solid which was dissolved in acetone and concentrated (3×). The light yellow solid was collected and dried under to provide the title compound as a 1:1 mixture of rotational diastereoisomers (75.1 mg, 0.133 mmol, 23%): mp 201-204° C.; 1H NMR of mixture (400 MHz, CDCl3) δ 8.56 (s, 2H), 8.18 (dd, J=10.8, 7.4 Hz, 6H), 7.84-7.73 (m, 8H), 7.45-7.30 (m, 8H), 7.30-7.23 (m, 2H), 7.20 (d, J=6.7 Hz, 1H), 7.12 (dd, J=7.8, 1.2 Hz, 1H), 4.43-4.33 (m, 1H), 4.16 (dd, J=12.6, 6.3 Hz, 1H), 3.48 (dt, J=13.3, 6.7 Hz, 1H), 3.37 (dd, J=10.8, 6.2 Hz, 1H), 3.24 (dt, J=13.7, 6.9 Hz, 1H), 3.08-2.92 (m, 3H), 1.33-1.16 (m, 18H); ESIMS m/z 566 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:10]1[CH2:14][CH2:13][C:12](=O)[CH2:11]1>C(O)C>[O:10]1[CH2:14][CH2:13]/[C:12](=[N:9]\[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])/[CH2:11]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N/N=C1\CCOC1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A solution of hydrazinecarboxylic acid tert-butyl ester (8.85 g, 67 mmol) in ethanol (30 mL) was added to a solution of dihydro-furan-3-one (5.78 g, 67 mmol) in ethanol (100 mL). This mixture was heated at reflux for 19 hours, then cooled to room temperature and concentrated under reduced pressure. The resulting crude mixture was partitioned between water (100 mL) and dichloromethane (100 mL). The aqueous layer was basified and extracted with dichloromethane (50 mL). The combined organic extracts were dried over magnesium sulphate, filtered, and evaporated under reduced pressure to give an oil (10.56 g, 79%). APCI MS m/z 201 [MH]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1CCNCC1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)c(F)c1
Temperature: 25 °C

Procedure:
3,4-Difluoronitrobenzene (1.4 mL, 2.01 g, 12.7 mmol) in piperidine (4 mL, 40.4 mmol) was heated in a sealed tube at 130° C. for 2 hours. The mixture was allowed to cool to room temperature and poured into H2O (150 mL). The title compound was separated by pipette. 1H NMR (300 MHz, DMSO-d6) δ 7.95–8.01 (m, 2H), 7.11–7.18 (m, 1H), 3.26–3.29 (m, 4H), 1.62–1.68 (m, 6H); MS (ESI+) m/z 225 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][C:14]=1[F:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][Cl:3])=[CH:15][C:14]=1[F:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccc(OCc2ccccc2)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1cc(CCl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (5 mL) was added to solution of (4-benzyloxy-3-fluoro-phenyl)methanol (CAB03017, 6.80 g, 29.28 mmol) in dichloromethane (50 mL). The solution was stirred for 1 h at room temperature and concentrated under reduced pressure. Then diethyl ether (100 mL) and water (20 mL) were added. The organic layer was separated, washed with conc. sodium bicarbonate solution (10 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and precipitated by addition of hexane (ca 50 mL). The precipitate was filtered off and dried under high vacuum. Yield: 7.01 g (95%) white powder. 1H-NMR (400 MHz, CDCl3) δ=4.52 (s, 2H, —CH2Cl), 5.15 (s, 2H), 6.96 (dd, J=8.2, 8.2 Hz, 1H), 7.04-7.06 (m, 1H), 7.15 (dd, J=11.7, 2.4 Hz, 1H), 7.31-7.45 (m, 5H). LRMS (FAB+): 91 (100), 215.0 (10), 250.0 (16, [M]+).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl[CH:7](Cl)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:17]=1[NH:27][NH2:28]>O.C(OCC)C>[Cl:22][C:20]1[C:19]([O:23][CH:24]([CH3:25])[CH3:26])=[CH:18][C:17]([NH:27][N:28]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[C:16]([F:15])[CH:21]=1
Reactant: O=C(C(Cl)Cl)C(F)(F)F
Reactant: CC(C)Oc1cc(NN)c(F)cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)Oc1cc(NN=CC(=O)C(F)(F)F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 5.3 g of sodium acetate dissolved in 100 ml of water was added 4.4 g of 1,1-dichloro-3,3,3-trifluoroacetone under ice cooling, and the reaction was allowed to proceed at 90° C. for 30 minutes. The reaction solution was left cooling to room temperature, to which a solution of 5.8 g of 2-fluoro-4-chloro-5-isopropoxyphenyl-hydrazine dissolved in 20 ml of diethyl ether was added, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, washed once with 10 ml of saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and evaporated to remove the diethyl ether to give 6.5 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-isopropoxyphenylhydrazone), compound 3-3.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:26]Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:26][C:9]1[C:10]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=2)=[N:11][N:12]([CH3:13])[C:8]=1[C:7]([CH3:25])([CH3:24])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1C(C)(C)O[SiH2]C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)c(Br)c1C(C)(C)O[SiH2]C(C)(C)C
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
A solution of 5-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole (162 mg, 437 μmol) in dichloromethane (1.7 ml) was added within 10 min to a mixture of bromine (20 μl, 480 μmol) and sodium carbonate (93 mg, 880 μmol) in dichloromethane (4.3 ml) at 0° C. under an argon atmosphere. After stirring at 0 to 5° C. for 1 h and then at ambient temperature for 1 h, the mixture was quenched with water (5 ml) and extracted two times with dichloromethane. The combined extracts were washed with aqueous saturated NaHSO3 solution and brine/ice water 1/1 and dried over sodium sulfate. Removal of the solvent under reduced pressure left off-white crystals which were purified by column chromatography (silica gel, heptane/AcOEt) to give 90 mg (0.2 mmol, 46%) of the title compound as colorless crystals.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:21])[C:4]2[C:9]([O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:8]1[NH:18][N:19]=[CH:20][C:7]1=[CH:6][CH:5]=2.[H-].[Na+].I[CH3:25]>CN(C=O)C>[I:1][C:2]1[C:3](=[O:21])[C:4]2[C:9]([O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:8]1[N:18]([CH3:25])[N:19]=[CH:20][C:7]1=[CH:6][CH:5]=2
Reactant: CI
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.6 %

Procedure:
To a solution of 7-iodo-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one (100 mg, 0.26 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion in oil, 30 mg, 0.77 mmol) and the reaction stirred at RT. After 5 min, iodomethane (0.06 mL, 0.90 mmol) was added and the reaction stirred at RT for 6 h. The reaction mixture was quenched by addition of water (3 mL) and extracted with EtOAc (×2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 100% EtOAc in cyclohexane) to afford the title compound (55 mg, 55%), LCMS (Method B): RT=3.87 min, [M+H]+=403. 7-iodo-2-methyl-8-phenyl-2H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was also isolated.