Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[NH:10]N.[N:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=O)[CH2:14][CH2:13]2>Cl.C(O)(=O)C>[Br:2][C:3]1[C:4]2[NH:10][C:15]3[CH:16]4[CH2:19][CH2:20][N:12]([CH2:13][C:14]=3[C:5]=2[CH:6]=[C:7]([F:9])[CH:8]=1)[CH2:18][CH2:17]4
Reactant: O=C1CCN2CCC1CC2
Reactant: NNc1ccc(F)cc1Br
Agent: Cl
Solvent: CC(=O)O
Product: Fc1cc(Br)c2[nH]c3c(c2c1)CN1CCC3CC1
Temperature: 80 °C

Procedure:
(2-Bromo-4-fluorophenyl)hydrazine hydrochloride (1.14 g, 4.72 mmol; Enamine) was suspended in HCl-acetic acid (1.0 M, 25 mL; Aldrich). The product of Example 1A (684 mg, 4.91 mmol) was added and the reaction was heated to 80° C. for 5 hours. The reaction was then allowed to cool and then concentrated. The product was triturated with acetonitrile and isolated by filtration, washing with additional acetonitrile (2×10 mL). The solid was partitioned between 1.0 M NaOH (50 mL) and CHCl3 (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.05-2.11 (m, 4H), 3.01-3.14 (m, 3H), 3.19-3.26 (m, 2H), 4.17 (s, 2H), 6.96-7.04 (m, 2H); MS (DCI/NH3) m/z 309/311 (M+H)+. Anal. Calcd. for C14H14BrFN2: C, 54.39; H, 4.56; N, 9.06. Found: C, 54.04; H, 4.28; N, 8.90.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][C:13]2([CH3:20])[CH3:19].O>C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([N:1]=[O:2])[CH2:14][C:13]2([CH3:20])[CH3:19]
Reactant: CC(C)CCON=O
Reactant: CC1(C)CNc2ccc(F)cc21
Solvent: O
Solvent: ClCCl
Product: CC1(C)CN(N=O)c2ccc(F)cc21
Yield: 96 %

Procedure:
Isoamyl nitrite (3.4 mL, 25.42 mmol) is added to a solution of 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole (3.75 g, 22.69 mmol) in DCM. The mixture is refluxed overnight. The mixture is cooled and portioned between DCM and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford 5-fluoro-3,3-dimethyl-1-nitroso-2,3-dihydro-1H-indole (4.23 g, 96%) as a solid. MS: 195 (M+H). 1H NMR (300 MHz, CD3Cl)): δ 7.77 (dd, 1H), 7.08-6.98 (m, 2H), 3.94 (s, 2H), 1.39 (s, 6H).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([I:14])[CH:7]=1.O>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:14])[CH:7]=1
Reactant: COc1ccc(Cl)cc1I
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Cl)cc1I
Temperature: 20 °C

Procedure:
Boron tribromide (1349 g) was added to a solution of 4-chloro-2-iodoanisole (1025 g) in dichloromethane (10.3 L) under nitrogen at such a rate that the temperature remained at 0-5° C. The solution was then warmed to 20° C. and stirred for c. 19 h until the reaction was complete by HPLC. This organic solution was added to water (8.2 L) and the mixture was cooled to 5° C. to 10° C. DCM (770 ml) was added and the resulting biphasic mixture was then stirred at 5° C. for 15 min before being warmed to 22° C. and then finally stirred at 22° C. for 20 min before separating the phases. The separated organic phase was washed with aqueous saturated sodium bicarbonate (3.1 L), water (3.1 L) and then evaporated on a Buchi to give the title compound. (963.6 g)
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:27])=[C:15]([CH:18]=[CH:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]>C(OC(C)C)(C)C>[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH:18]=[CH:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnc3)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(C=Cc3cccnc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of benzhydryl 7-phenylacetamido-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (cis-trans mixture) (5.9 g), anisole (6 ml) and trifluoroacetic acid (20 ml) was stirred at ambient temperature for 30 minutes. The reaction mixture was added to di-iso-propylether (300 ml). The precipitate was collected by filtration, washed with di-iso-propylether to give 7-phenylacetamido-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid trifluoroacetate (cis-trans mixture) (2.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([OH:16])[CH:8]=1.O.[NH2:21][NH2:22]>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:21][NH2:22])=[O:12])=[C:9]([OH:16])[CH:8]=1
Reactant: NN
Reactant: O=C(O)c1ccc(OCc2cccc(Br)c2)cc1O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)c1ccc(OCc2cccc(Br)c2)cc1O
Temperature: 120 °C
Yield: 16.2 %

Procedure:
A slurry of 4-(3-bromo-benzyloxy)-2-hydroxy-benzoic acid (2.15 g; 6.4 mmol) in MeOH (10 mL) was added hydrazine hydrate (3 mL; 62 mmol) and heated to 120° C. in a sealed metal cylinder for 40 min. The cylinder was cooled on ice and the slurry diluted with THF in order to dissolve precipitate. The clear solution was evaporated onto SiO2, and purified by filtration through a plug of Silica gel (SiO2—PE80-100° C./EtOAc=4:1; EtOAc then EtOAc/CH2Cl2=3:2) to yield after evaporation 0.9 g (42%). The compound was further purified by crystallization from MeOH/THF to yield 350 mg pure product. Mp. 201-203° C.; MS (ESI−): 335/337 (MH−).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[S:11]2(=[O:19])=[O:18])[CH:3]=1.Cl>C(Cl)Cl.C(OCC)(=O)C.C(O)C.[Pd]>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([N:10]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[S:11]2(=[O:19])=[O:18])[CH:3]=1
Reactant: CN1C(C)(C)CN(c2cc(F)ccc2C#N)S1(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: CN1C(C)(C)CN(c2cc(F)ccc2CN)S1(=O)=O
Reaction time: 22 h

Procedure:
To a solution of 4-fluoro-2-(4,4,5-trimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)benzonitrile (3.34 g, 11.8 mmol) in CH2Cl2 (30 mL), ethyl acetate (30.0 mL) and ethanol (30.0 mL) was added 1N HCl (12 mL) followed by 10% palladium on carbon (0.377 g, 3.54 mmol). The mixture was shaken under H2 at 50 psi for 22 h then filtered over CELITE® and concentrated. The solids were triturated with H2O and removed by filtration. The aqueous solution was washed with ethyl acetate and lyophilized to give the title compound, as the HCl salt, as a white powder (3.44 g, 90% yield). LCMS (M+H) calcd for C12H19FN3O2S: 288.11; found: 288.19. 1H NMR (300 MHz, DMSO) δ: 8.35 (2H, brs), 7.71 (1H, dd, J=8.6, 6.4 Hz), 7.54 (1H, dd, J=9.9, 2.6 Hz), 7.43 (1H, td, J=8.4, 2.6 Hz), 4.19 (2H, s), 3.75 (2H, s), 2.63 (3H, s), 1.35 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH2:6][CH:7]=1.[Li+].[CH3:16]C([N-]C(C)C)C.CI>C1COCC1.CC(OC)(C)C>[CH3:1][C:2]1([CH3:16])[CH:7]=[CH:6][CH2:5][C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[C:3]1=[O:14]
Reactant: CC(C)=CCC1(C)CCC=C(C)C1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CI
Product: CC(C)=CCC1(C)CC=CC(C)(C)C1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2,6-Dimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enone (5.00 g, 26 mmol) was added to a solution of LDA (prepared from diisopropylamine (3.15 g, 31.2 mmol) and n-BuLi (1.6M in hexane, 19.5 ml, 31.2 mmol)) in THF (50 ml) at −78° C. The mixture was stirred for 1 h at −78° C. Methyl iodide (5.54 g, 39 mmol) was added and the solution was allowed to warm to room temperature over night. The mixture was diluted with MTBE and washed with portions of H2O and brine, dried (MgSO4) and concentrated in vacuo to yield 7 g of a slightly yellow oil which was distilled (bp.42° C./0.005 mbar) to give 4.5 g (84%) of an olfactorily clean oil. 1H-NMR (400 MHz, CDCl3): 5.72-5.68 (m, 1H), 5.63-5.59 (m, 1H), 5.06-4.99 (m, 1H), 2.36-2.08 (m, 4H), 1.70 (s, 3H), 1.59 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.07 (s, 3H) ppm. GC/MS (EI): 206 (M+, 15), 191 (8), 137 (19), 123 (25), 109 (100), 96 (34), 91 (9), 81 (28), 67 (24), 41 (33). IR (ATR): 3023s, 2966s, 2926m, 1703vs, 1456s, 1376m, 1203w, 1033s, 713s cm−1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH:20]=O.N1CCCCC1>C(O)C>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH:20]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=Cc1cc2ccccc2[nH]1
Temperature: 95 °C

Procedure:
A mixture of 2-oxindole (133 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was heated in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven for overnight to give 3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](I)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:12]1([C@@:15]2([OH:23])[C@H:19]([CH2:20][CH3:21])[NH:18][C:17](=[O:22])[CH2:16]2)[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:18]2[C:17](=[O:22])[CH2:16][C@:15]([CH:12]3[CH2:14][CH2:13]3)([OH:23])[C@@H:19]2[CH2:20][CH3:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(I)ccc(C#N)c1Cl
Reactant: CC[C@@H]1NC(=O)C[C@@]1(O)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@@H]1N(c2ccc(C#N)c(Cl)c2C)C(=O)C[C@@]1(O)C1CC1

Procedure:
Using 2-chloro-4-iodo-3-methylbenzonitrile (478 mg), (4R, 5S) -4-cyclopropyl-5-ethyl-4-hydroxypyrrolidin-2-one (350 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (153 mg), tris(dibenzylideneacetone)dipalladium(0) (79 mg) and cesium carbonate (786 mg), and in the same manner as in Example 62, the title compound was obtained as colorless crystals (yield: 78 mg, 14%).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[NH:19][NH2:20].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:7](=[N:20][NH:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)NN
Reactant: COc1ccc(CC(=O)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)NN=C(Cc1ccc(OC)cc1)c1ccccc1
Yield: 76.8 %

Procedure:
A solution of 1-phenyl-2-(4-methoxyphenyl)-ethanone (Aldrich) (22.6 g, 0.1 mol), ethyl carbazate (12.5 g, 0.12 mol) and a spatula tip of TsOH in toluene (200 ml) was heated to reflux, and water was azeotropically removed. The reaction was complete (by TLC) after 4 hours. The solvent was removed under reduced pressure, and the crude solid was chromatographed, SiO2 (400 g), eluting with Hex/EtOAc, 7/3, affording 9 (24.0 g, 76.9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.1 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product as a yellow solid 2-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (74.3 mg, 65%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH:6][CH2:7][CH:8](O)[C:9]2[C:14]([F:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[CH:10]=2)=[CH:2]1.S(=O)(=O)(O)O.F[C:27](F)(F)C(O)=O>>[F:15][C:14]1[C:9]([CH:8]2[CH2:7][NH:6][CH2:3][C:4]3[CH:27]=[CH:2][S:1][C:5]2=3)=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=1
Reactant: COc1cc(F)c(C(O)CNc2ccsc2)cc1OC
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: COc1cc(F)c(C2CNCc3ccsc32)cc1OC

Procedure:
1.16 g of α-[[(3-thienyl)amino]methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol was dissolved in 11 ml of trifluoroacetic acid and after adding thereto 0.31 ml of conc. sulfuric acid under ice cooling, the mixture was stirred for 4 hours. The reaction solution was concentrated, and chloroform and water were added to the residue. The mixture was basified by addition of 10 ml of conc. aqueous ammonia under ice cooling. The chloroform layer was collected after a separating procedure, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethanol, affording 0.76 g of 7-(6-fluoro-3,4-dimethoxyphenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (m.p. 108°-111° C.).
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl[C:35]1[N:40]=[N:39][C:38]([S:41](F)(=[O:43])=[O:42])=[CH:37][CH:36]=1.NN.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]1([C:7]2[N:11]([S:41]([C:38]3[N:39]=[N:40][CH:35]=[CH:36][CH:37]=3)(=[O:43])=[O:42])[CH:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(F)c1ccc(Cl)nn1
Reactant: CCOC(=O)c1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: NN
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2cccnn2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
Ethyl 5-phenyl-1H-pyrrole-3-carboxylate (1.06 g) was dissolved in tetrahydrofuran (30 mL), sodium hydride (60% in oil, 300 mg) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (1.52 mL) was added and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridazine-3-sulfonyl fluoride (1.28 g) was added and the reaction mixture was stirred at room temperature for 30 min. Hydrazine (1.60 g) was added and the reaction mixture was stirred at room temperature for 15 min. Saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), manganese dioxide (75% chemically treated product, 5.0 g) was added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→1:1) to give the title compound (yield 613 mg, yield 24% (containing impurity)).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[N:12][N:13]([CH2:15][CH2:16][F:17])[N:14]=1)(C)(C)C.[ClH:19]>ClCCl.O1CCOCC1>[ClH:19].[F:17][CH2:16][CH2:15][N:13]1[N:12]=[N:11][C:10]([CH2:9][CH2:8][NH2:7])=[N:14]1
Reactant: CC(C)(C)OC(=O)NCCc1nnn(CCF)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCc1nnn(CCF)n1
Reaction time: 1 h

Procedure:
A solution of {2-[2-(2-Fluoro-ethyl)-2H-tetrazol-5-yl]-ethyl}-carbamic acid tert-butyl ester (1.0 g, 3.9 mmol) in dichloromethane (30 ml) was treated with a solution of 4M HCl in dioxane (31 ml) and the reaction mixture stirred for 1 hour. The solvent was evaporated to yield the titled product as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[O:10][C:9](=[O:17])[CH:8]=[CH:7]2)[CH:2]=[CH2:3].S(=O)(=O)(O)O>>[CH3:3][CH:2]1[O:14][C:13]2=[C:12]([O:15][CH3:16])[C:11]3[O:10][C:9](=[O:17])[CH:8]=[CH:7][C:6]=3[CH:5]=[C:4]2[CH2:1]1
Reactant: C=CCc1cc2ccc(=O)oc2c(OC)c1O
Agent: O=S(=O)(O)O
Product: COc1c2c(cc3ccc(=O)oc13)CC(C)O2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A sample of 1.0 g. (4.31 mmoles) of 6-allyl-7-hydroxy-8-methoxycoumarin was dissolved in 20 ml. of conc. sulfuric acid at 25°. After 10 min, the solution was diluted with ice water. The mixture was extracted with methylene chloride, dried over sodium sulfate, and evaporated to yield 90 g. of residue. This was filtered through a column of silica gel, eluting with benzene/ethyl acetate, 4:1, to afford, upon evaporation of the filtrate, pure 2-methyl-9-methoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one as a white solid. Recrystallization from ethanol yielded an analytical sample, mp 115°-116°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.[CH:26]12[NH:37][CH:33]([CH2:34][O:35][CH2:36]1)[CH2:32][C:31]1[C:27]2=[CH:28][O:29][N:30]=1>>[CH3:18][O:17][C:15]([C:14]1[C@H:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[N:10]=[C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:12][C:13]=1[CH2:19][N:37]1[CH:33]2[CH2:34][O:35][CH2:36][CH:26]1[C:27]1[C:31]([CH2:32]2)=[N:30][O:29][CH:28]=1)=[O:16]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: c1onc2c1C1COCC(C2)N1
Product: COC(=O)C1=C(CN2C3COCC2c2conc2C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 1a in Scheme 3 by using methyl (4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate C (200 mg) and 4,10-Dioxa-5,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2,5-diene 104a (100 mg). 15 mg of the title compound was isolated as yellow powder.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCCCc1ccccc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 92.1 %

Procedure:
A solution of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.50 mmol), TEA (0.076 g, 0.751 mmol) and 4-phenylbutylamine (0.097 g, 0.65 mmol) in MeCN (3 mL) was heated in a microwave reactor at 120° C. for 10 mins. The mixture was evaporated and the residue was purified by silica gel column chromatography using a 85:15 mixture of heptane and EtOAc as eluant, to give the title compound (0.19 g, 92%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.52-7.47 (m, 2H), 7.45-7.40 (m, 3H), 7.31-7.26 (m 2H), 7.22-7.17 (m, 1H), 7.08 (d, 2H), 5.26 (t, 1H), 2.88-2.81 (m, 2H), 2.49-7.43 (m 2H), 1.75 (s 9H), 1.48-1.36 (m 4H); 13C NMR (125 MHz, CDCl3) δ 159.9, 141.8, 135.3, 131.9, 129.8, 128.8, 128.6, 128.5, 126.2, 125.3, 107.0, 61.7, 44.1, 35.5, 29.2, 28.4, 27.9; Mass Spectrum: M−H+ 413.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH:28]=O)=[CH:22]3)[CH2:15][CH2:14][CH2:13][CH2:12]1.N1CCCCC1>C(O)C>[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH:28]=[C:3]2[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]2=[O:10])=[CH:22]3)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 81.7 %

Procedure:
A mixture of oxindole (26.6 mg, 0.2 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (52 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 61 mg (81%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH:9]1[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])=O)(C)(C)C.[ClH:30]>ClCCl.C(OCC)C>[ClH:30].[O:12]1[C:11]2([CH2:16][CH2:17][NH:8][CH:9]([CH2:18][N:19]3[C:20](=[O:29])[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]3=[O:28])[CH2:10]2)[O:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1CN1C(=O)c3ccccc3C1=O)OCCO2
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CC1CC2(CCN1)OCCO2
Reaction time: 62 h
Yield: 90 %

Procedure:
To the above 7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.1 g, 2.7 mmol) dissolved in dichloromethane (6 ml) was added 1.0 N hydrogen chloride in diethyl ether (50 ml) and the solution kept at ambient temperature for 62 h. The precipitate was filtered off and washed with diethyl ether and dried with nitrogen which afforded 0.83 g (90%) of 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione hydrochloride as a solid.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][O:11][CH2:12][CH2:13][O:14]C(=O)C)[CH:2]=1.C[O-].[Na+]>CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][O:11][CH2:12][CH2:13][OH:14])[CH:2]=1
Reactant: CC(=O)OCCOCn1cnc2cccnc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCCOCn1cnc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
0.79 g (3.36 mmol) acetic acid 2-(3H-imidazo[4,5-b]pyridin-3-ylmethoxy)-ethyl ester were dissolved in 10 ml methanol and 10 mg (1.85 mmol) sodium methoxide were added. The mixture was stirred at room temperature for 3 hours. The orange mixture was concentrated in vacuo to afford 0.64 g (99%) of crude product. MS (EI): 193.2, 163.2, 148.2, 133.2.