Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30].O>C(Cl)Cl>[C:28]([O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:4]2[C:5]3[S:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)[CH:15]=1)(=[O:31])[CH:29]=[CH2:30]
Reactant: C=CC(=O)Cl
Reactant: Oc1cccc(-c2cccc3c2sc2ccccc23)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)Oc1cccc(-c2cccc3c2sc2ccccc23)c1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
1.03 g of the thus obtained 3-(4-dibenzothiophenyl)phenol is placed in a round bottom flask and suspended in 15 mL of methylene chloride; after ice cooling the flask, 0.45 g of triethylamine is added; 0.40 g of acryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 10 mL of water is added; the mixture is vigorously stirred; an aqueous layer is then removed; the aqueous layer is washed with methylene chloride and ethyl acetate, respectively and then gathered with the original methylene chloride solution; and the mixture is dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and the concentrate is separated by a silica gel column (eluate: hexane/ethyl acetate=80/20 (volume ratio)) to concentrate a component having an Rf of 0.50, thereby obtaining 0.90 g (yield: 73%) of the foregoing white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 6.03 (dd=1.2 & 10.4 Hz, 1H), 6.36 (dd=10.4 & 17.2 Hz, 1H), 6.64 (dd=1.2 &17.2 Hz, 1H), 7.20 to 7.24 (m, 1H), 7.44 to 7.55 (m, 6H), 7.62 to 7.65 (m, 1H), 7.82 to 7.85 (m, 1H), 8.14 to 8.19 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](Br)[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[O:13][CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22]1[CH2:26]OC[CH2:23]1>O.CCOC(C)=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>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:22]([CH3:26])=[CH2:23])[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[O:13][CH3:14]
Reactant: COC(=O)c1cc(Br)c(OC)cc1OC
Reactant: C1CCOC1
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: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)c1cc(C(=O)OC)c(OC)cc1OC

Procedure:
To potassium isopropylidene trifluoroborate (4.87 g, 32.7 mmol) and 5-bromo-2,4-dimethoxybenzoic acid methyl ester (7.5 g, 27.3 mmol) in THF (195 ml) was added Cs2CO3 (26.6 g, 81.8 mmol) in water (39 ml). The reaction was degassed and Pd(PPh3)4 (1.58 g, 1.36 mmol) added. The reaction was heated at reflux for three days then quenched by adding water and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to leave an orange solid. The product was taken up in EtOAc again and the precipitate filtered. The filtrate was evaporated to dryness to yield 5-isopropenyl-2,4-dimethoxy-benzoic acid methyl ester (6.2 g). 1H NMR (Me-d3-OD) 7.68 (1H, s), 6.66 (1H, s), 5.10-5.08 (1H, m), 5.02-5.00 (1H, m), 3.93 (3H, s), 3.92 (3H, s), 3.84 (3H, s), 2.08-2.06 (3H, m). MS: [M+H]+ 237.
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([O-])=[CH:10][C:11](=O)[C:12]([O:14]CC)=[O:13])[CH:6]=[CH:5][N:4]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:44]=[C:45]([NH:49][NH2:50])[CH:46]=[CH:47][CH:48]=1>>[Cl:42][C:43]1[CH:44]=[C:45]([N:49]2[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([Cl:2])[CH:8]=3)=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[N:50]2)[CH:46]=[CH:47][CH:48]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1ccnc(Cl)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2ccnc(Cl)c2)n(-c2cccc(Cl)c2)n1

Procedure:
560 mg (2.14 mmol) of the compound of Example 19A is reacted analogously to the synthesis of the compound of Example 20A with 422 mg (2.36 mmol) of 3-chlorophenylhydrazine hydrochloride. After hydrolysis, 494 mg (69% of theory) of the title compound is obtained.
Reaction SMILES: N[C:2]1[C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.N.Cl.CO>O1CCCC1.N1C=CC=CC=1>[NH:8]1[C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=[N:9]1
Reactant: Nc1cccc2nn[nH]c12
Agent: Cl
Agent: N
Solvent: c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the above acid chloride (ca. 0.02M) in tetrahydrofuran (10 ml) was added over 8 minutes to a stirred solution of 7-aminobenzotriazole (2.5 g, 0.019M) in pyridine (20 ml). The mixture was stirred at room temperature for 4 hours, then 0.88M ammonia (0.5 ml) was added and stirring was continued for another 20 minutes. The mixture was poured into ice/water (200 ml) to give an oil which soon solidified. 10M Hydrochloric acid (25 ml) was added and the acidified mixture was stirred for 5 minutes before the resulting pink solid was filtered off, washed with water and dried, 5.8 g. The solid was added to methanol (25 ml) and the suspension was stirred at room temperature for 1 hour. Filtration of the mixture resulted in removal of most of the colour from the solid, which was further washed with methanol and dried, 4.3 g. The solid was heated briefly on a steam-bath with tetrahydrofuran (50 ml) to give a cloudy solution. This was cooled and filtered through Kieselguhr and the filtrate was concentrated under reduced pressure to leave an off-white solid. Methanol (25 ml) was added and the mixture was stirred at room temperature for 2 hours, then the resulting white solid was filtered off, washed with methanol and dried to give B1-1, 15 g (52%). The positive and negative ion electrospray mass spectra were consistent with the structure of the required product. LCMS indicated purity of >98%, which was also supported by the 1H-nmr spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:22]=[CH:23][CH:24]=[N:25]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:25][CH:24]2[CH2:22][CH2:23]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Bromo-benzoic acid (2.5116 g, 12.5 mmol) and HATU (5.2213 g, 13.7 mmol) were dissolved in DMF (40 mL). DIEA (4.572 mL, 26.2 mmol) was added, and the mixture was allowed to stir at ambient temperature for 15 minutes. Then cyclopropylamine (0.866 mL, 12.5 mmol) was added, and the reaction was stirred at ambient temperature overnight. The solvent was removed, and the crude was purified via silica gel chromatography to give the desired product.
Reaction SMILES: C(S)C.[H-].[Na+].CN(C=O)C.[S:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=4)[CH:22]=[N:21][C:20]=23)=[CH:12]1>O>[S:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=4)[CH:22]=[N:21][C:20]=23)=[CH:12]1
Reactant: COc1ccc(-c2cnc3c(-c4ccsc4)cnn3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Solvent: O
Product: Oc1ccc(-c2cnc3c(-c4ccsc4)cnn3c2)cc1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 23.4 %

Procedure:
Ethanethiol (30 mg, 36 uL) was added dropwise over 1 min to a suspension of sodium hydride (23 mg, 0.98 mmol) in 10 dry DMF (2 mL) under argon. After 15 min, the compound of example 2 (50 mg, 0.16 mmol) was added and the reaction mixture was heated at 150° C. for 1.5 h. The resulting brown solution was cooled, poured into water (25 mL) and washed with ethyl acetate (2×25 mL). The combined organics were dried (Na2SO4), is concentrated, and purified by flash chromatography (40% EtOAc/Hexanes) to give the title compound as a yellow solid [11 mg, 23%, Rf=0.12 (40% EtOAc/Hexanes)]: 1H NMR (CD3OD) δ8.96 (d, 1H, J=2.4Hz), 8.85 (d, 1H, J=2.2Hz), 8.44 (s, 1H), 7.94 (dd, 1H, J=2.9, 1.2Hz), 7.74 (dd, 1H, J=4.9, 1.2Hz), 7.56 (d, 2 H, J=8.8Hz), 7.46 (dd, 1H, J=4.9, 2.9Hz), 6.94 (d, 2H,J=8.6Hz).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:46][CH:47]1[C@H:51]2[C@H:52](OC3CCCCO3)[N:53](C(OC(C)(C)C)=O)[C:54]3[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:55]=3[C:56](=[O:57])[N:50]2[CH2:49][CH2:48]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]1[C@H:19]2[C@H:20](OC3CCCCO3)[N:21](C(OC(C)(C)C)=O)[C:22]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=3[C:24](=[O:25])[N:18]2[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:46][CH:47]1[C@@H:51]2[CH:52]=[N:53][C:54]3[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:55]=3[C:56](=[O:57])[N:50]2[CH2:49][CH2:48]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]1[C@@H:19]2[CH:20]=[N:21][C:22]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=3[C:24](=[O:25])[N:18]2[CH2:17][CH2:16]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 88.2 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8d (174 mg, 0.17 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9d (86 mg, 0.15 mmol, 88%) as a solid: [α]20D=+500° (c=0.09, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.39-1.55 (m, 4H, 14-H, 14′-H), 1.72-1.89 (m, 4H, 13-H, 13′-H), 1.91-2.05 (m, 4H, 2-H, 2′-H), 2.17-2.31 (m, 4H, 1-H, 1′-H), 3.45-3.56 (m, 2H, 3-H, 3′-H), 3.62-3.69 (m, 2H, 11a-H, 11a′-H), 3.70-3.79 (m, 2H, 3-H, 3′-H), 3.83 (s, 6H, 7-OMe, 7′-OMe), 3.95-4.13 (m, 4H, 12-H, 12′-H), 6.73 (s, 2H, 9-H, 9′-H), 7.43 (s, 2H, 6-H, 6′-H), 7.58 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.7, 29.0, 29.6, 46.6, 53.7, 56.0, 69.0, 109.6, 112.5, 120.2, 140.5, 147.1, 151.7, 162.8, 164.6; IR (neat): 3385, 2945, 1622, 1599, 1506, 1447, 1387, 1261, 1217, 1093 cm−1; MS (FAB) m/z (relative intensity) 639 ([M+2×MeOH]+., 4), 607 ([M+MeOH]+., 12), 575 (M+., 100).
Reaction SMILES: O=[C:2]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)[CH2:3][CH2:4][C:5](O)=[O:6].O.[NH2:24][NH2:25]>C(O)C>[O:6]=[C:5]1[CH2:4][CH2:3][C:2]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:25][NH:24]1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1c(-c2ccccc2)nn2ccccc12
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2c(-c3ccccc3)nn3ccccc23)=NN1
Yield: 70.5 %

Procedure:
A mixture of 4-oxo-4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)butyric acid (1.71 g), hydrazine monohydrate (1.46 g) and ethanol (17 ml) was heated under reflux for 1 hour. Ethanol was evaporated in vacuo. Water (20 ml) was added to the residue, acidified with 5% hydrochloric acid and extracted with chloroform (25 ml×3). The combined extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give crystals of 3-(3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (1.19 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:17])C(=O)C1>ClCCl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:17])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#Cc1cc(Br)ccc1N
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
2-Aminobenzonitrile (5.0 g, 42.3 mmol) was taken into dichloromethane (60 mL). NBS (7.54 g, 42.3 mmol) was added and stirred at 0° C. for 3 h. The reaction mixture was diluted with dichloromethane and washed with brine, dried over MgSO4. The crude product was purified by column chromatography (hexane/ethyl acetate=10/1) to afford the titled compound (7.20 g, 87%). 1H NMR (400 MHz, DMSO-d6): δ 6.22 (s, 2H), 6.75 (d, J=9.2 Hz, 1H), 7.42 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.58 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]=5[NH2:25])[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]=5[NH:25][C:27](=[O:34])[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(N)c45)[nH]c3c2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(NC(=O)c6ccccc6)c45)[nH]c3c2)CC1
Reaction time: 8 h

Procedure:
3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-4-ylamine as dissolved in CH2C2 and benzoyl chloride (1.1 equivalent) is added followed by diisopropylethylamine (1.1 equivalent). The resulting mixture is stirred overnight. The solution is then concentrated and the resulting residue is purified by preparatory HPLC to provide the title compound.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12](=O)[CH2:13][C:14](OCC)=[O:15])=[C:7]([F:20])[CH:6]=1.O>C(O)COCCO>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:3][N:2]([CH3:1])[C:14](=[O:15])[CH:13]=2)=[C:7]([F:20])[CH:6]=1
Reactant: CCOC(=O)CC(=O)c1cc(C)c(Cl)cc1F
Reactant: CNN
Solvent: O
Solvent: OCCOCCO
Product: Cc1cc(-c2cc(=O)n(C)[nH]2)c(F)cc1Cl
Reaction time: 6 h

Procedure:
34.7 g (0.75 mol) of methylhydrazine were added to a solution of 177 g (0.68 mol) of ethyl 3-(4-chloro-2-fluoro-5-methylphenyl)-3-oxopropionate in 500 ml of diethylene glycol. After 6 hours at 100° C., the mixture was poured into 4 l of water. The solids were subsequently removed and dried. Yield: 133 g; m.p.: 155-156° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]([CH3:23])[C:10]([CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)=[O:11].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2]([C:12]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[C:10](=[O:11])[N:9]2[CH3:23])=[CH:7][CH:6]=1
Reactant: CN(C(=O)C1CN(C(=O)OC(C)(C)C)C1)c1cc(Cl)ccc1Br
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: CN1C(=O)C2(CN(C(=O)OC(C)(C)C)C2)c2ccc(Cl)cc21
Temperature: 80 °C
Yield: 69.7 %

Procedure:
tert-butyl 3-((2-bromo-5-chlorophenyl)(methyl)carbamoyl)azetidine-1-carboxylate 7.57 (112 mg, 0.28 mmol), palladium acetate (6.6 mg, 0.03 mmol), tricyclohexylphosphine (8.4 mg, 0.03 mmol), and sodium t-butoxide (42 mg, 0.44 mmol) were added to a flask and system was evacuated and placed under argon. Dioxane (2 mL) was added and mixture was heated at 80° C. for 20 hours. After cooling to rt, mixture was poured into 50% saturated NH4Cl(aq) and extracted with ethyl acetate. Layers were separated and organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel column chromatography (0-30% ethyl acetate/hexanes) to yield tert-butyl 6′-chloro-1′-methyl-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate 7.58 (63 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:40]([O:43][CH2:44][CH2:45]Br)(=[O:42])[CH3:41]>CN(C=O)C>[C:40]([O:43][CH2:44][CH2:45][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:33])=[CH:17][C:18]=1[O:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)OCCBr
Reactant: COC(=O)C1(NC(=O)c2ccc(O)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of step 1 of example 254 (70 mg, 0.157 mmol) was dissolved in DMF (1 ml). Potassium carbonate (108 mg, 0.786 mmol) was added and subsequently 2-bromoethyl acetate (39 mg, 0.235 mmol). The mixture was stirred at room temperature for 2 h and then partitioned between EA and water. The aqueous phase was extracted with EA, and the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient).
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:22]=[C:21]2[C:10]([CH2:11][C:12]3[CH:16]=[CH:15][N:14]([CH2:17][C@H:18](O)[CH3:19])[C:13]=32)=[CH:9][CH:8]=1.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.C(OCC)C.CN(C)C=O.O>[N:30]([C@@H:18]([CH3:19])[CH2:17][N:14]1[CH:15]=[CH:16][C:12]2[CH2:11][C:10]3[C:21]([C:13]1=2)=[CH:22][C:7]([F:6])=[CH:8][CH:9]=3)=[N+:31]=[N-:32]
Reactant: C[C@@H](O)Cn1ccc2c1-c1cc(F)ccc1C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@@H](Cn1ccc2c1-c1cc(F)ccc1C2)N=[N+]=[N-]
Yield: 39.1 %

Procedure:
1.17 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.73 g of (R)-1-(7-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 4.2 ml of triethyl-amine in 60 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of diethyl ether, washed twice with 60 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of diethyl ether. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 973 mg of sodium azide and the reaction mixture was heated to 50° for 15 hours while stirring. After cooling, the solution was poured into 110 ml of water and extracted twice with 110 ml of diethyl ether each time and once with 60 ml of ethyl acetate. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 750 mg (39%) of (S)-1-(2-azido-propyl)-7-fluoro-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a colorless oil.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([CH3:21])([CH3:20])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)=[O:11])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C([O-])(=[S:48])C.[K+]>C(Cl)Cl.CC(N(C)C)=O.C(O)C>[SH:48][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([CH3:21])([CH3:20])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)=[O:11])[CH2:4]1
Reactant: CSc1ccc(C(=O)C(C)(C)N2CCCC(CO)C2)cc1
Reactant: CC([O-])=S
Agent: BrC(Br)(Br)Br
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: CSc1ccc(C(=O)C(C)(C)N2CCCC(CS)C2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.2 g (0.33 mol) of 2-(3-hydroxymethyl-piperidin-1-yl)-2-methyl-1-[4-(methylthio)-phenyl]-propan-1-one and 10.5 g of triphenylphosphine are dissolved in 60 ml of methylene chloride. 13.3 g of carbon tetrabromide is dissolved in 15 ml of methylene chloride and is added dropwise to the above solution at 5 ° C. After stirring for 2 h, the resulting solution is concentrated to give a slurry. This material is purified by column chromatography on silica gel with ethyl acetate-hexane (50-50) as an eluent, and an oily product is obtained. The resulting material is used for the next reaction. 13.0 g of the above oily product is dissolved in 80 ml of dried dimethylacetamide and 4.95 g of potassium thioacetate is added. After stirring for 2.5 h at 50 ° C., the reaction mixture is poured into ice-water and extracted with ethyl acetate. The combined organic layer is washed with saturated sodium chloride solution and died over MgSO4. The solvent is removed by evaporator and the crude oil is further purified by column chromatography on silica gel with ethyl acetate-hexane (10:90) as an eluent, and an oily product is obtained. The product is dissolved in 40 ml of ethanol and the solution is bubbled by nitrogen for 10 min. to remove oxygen. To the solution are added 10 ml of 2N sodium hydroxide solution and stirred at 0° C. for 1 h. After the reaction mixture is neutralized by adding 2N hydrochloric acid solution, the resulting solution is poured into 10 ml of water and extracted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride solution, and dried over MgSO4. After ethyl acetate is distilled off, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (5-95) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.02 (m, 1H), 1.26 (t, 1H), 1.29 (s, 3H), 1.30 (s, 3H), 1.43-1.55 (m, 1H), 1.61-1.66 (m, 2H), 1.87 (m, 1H), 2.06 (m, 1H), 2.23 (m, 1H), 2.40 (t, 2H), 2.52 (s, 3H), 2.69 (m, 1H), 2.88 (d, 1H), 7.22 (d, 2H), 8.49 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[O:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:4][C:3]=1[O:19][CH3:20].Cl[CH2:22][C:23]1[N:24]=[C:25](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:26][C:27]=1C>>[CH3:20][O:19][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[O:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])[CH:6]=[CH:7][C:2]=1[O:1][CH2:22][C:23]1[N:24]=[C:25](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:26][CH:27]=1
Reactant: COc1cc(CCCCC2OC(=O)NC2=O)ccc1O
Reactant: Cc1sc(/C=C/c2ccccc2)nc1CCl
Product: COc1cc(CCCCC2OC(=O)NC2=O)ccc1OCc1csc(/C=C/c2ccccc2)n1

Procedure:
In substantially the same manner as in Working Example 9, 5-[4-(4-hydroxy-3-methoxyphenyl)butyl]-2,4-oxazolidinedione was reacted with 4-chloromethyl-5-methyl-2-[(E)-styryl]thiazole to obtain 5-[4-[3-methoxy-4-[2-[(E)-styryl]-4-thiazolylmethoxy]phenyl]butyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.167-168° C.