Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33]>C1COCC1.C(OCC)(=O)C.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28]([C:37]4[CH:38]=[CH:39][C:34]([C:32]#[N:33])=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(I)cc2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(-c3ccc(C#N)cc3)cc2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[3-formyl-1-(4-iodophenyl)-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (294 mg, 0.553 mmol) and Pd(PPh3)4 (32 mg, 0.0277 mmol) are placed in a side-armed test tube and flushed with N2. Tetrahydrofuran (6.0 mL) and 1M aq potassium carbonate (0.6 mL) are added followed by a solution of 4-cyanobenzeneboronic acid (122 mg, 0.830 mmol) in THF (2.0 mL). After stirring at 70° C. for 8 hr the reaction is cooled, then dissolved in ethyl acetate, washed with water (2×10 mL), with brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography eluting with heptane-10 to 40% ethyl acetate. Product containing fractions are combined and concentrated to afford 4-[1-(4′-cyanobiphenyl-4-yl)-3-formyl-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid. TLC (heptane-30% ethyl acetate); RT=0.13; ESI/MS 451 [M-C(CH3)3]; NMR (CDCl3) 10.30 (1H, s); 8.28 (1H, d, J=9 Hz); 7.84 (6H, m); 7.55 (2H, d); 7.29 (3H, m); 3.34 (8H, m); 1.44 (9H, s).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>[Cl-].[Ca+2].[Cl-].C(Cl)Cl>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClC[C@@H]1CO1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and calcium chloride (1 g, 9 mmol) were added to 100 mL of methylene dichloride and stirred for 30 minutes. (S)-epichlorohydrin (21 g, 0.23 mol) was then added. The mixture was stirred at room temperature (30° C.) for 5 hours. Filtered, and the solvent was evaporated to provide 56 g of colorless oil in 95% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=3)=[CH:8]2)=[CH:4][CH:3]=1.C([Sn](=O)CCCC)CCC.[N:35]([Si](C)(C)C)=[N+:36]=[N-:37]>C1(C)C=CC=CC=1>[N:22]1[NH:35][N:36]=[N:37][C:21]=1[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[CH:10]=[CH:11][C:12](=[O:13])[N:7]([CH2:6][C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:8]=2)=[CH:15][CH:16]=1
Reactant: N#CCc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=c1ccc(-c2ccc(Cc3nn[nH]n3)cc2)cn1Cc1ccc(Cl)cc1
Yield: 37.5 %

Procedure:
According to Scheme 15 Method D: 2-(4-(1-(4-Chlorobenzyl)-1,6-dihydro-6-oxopyridin-3-yl)phenyl)acetonitrile (1 eq, 0.24 mmol, 0.08 g) was heated at 110° C. under nitrogen overnight with dibutyltin oxide (0.22 eq, 0.05 mmol, 0.01 g) and azidotrimethylsilane (6.0 eq, 1.43 mmol, 0.19 mL) in toluene (4 mL). The suspension was filtered and the filtrate concentrated under vacuo. The crude product was purified by chromatography on silica gel using MeOH/AcOEt 20/80 as eluent and recrystallised in diisopropyl ether to afford the title compound as a white solid (0.09 mmol, 35 mg, 39%).
Reaction SMILES: I[C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:11][C:10]1[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]([O:12][CH3:13])=[CH:3][C:2]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]([F:26])([F:25])[F:14]
Reactant: COc1cc(I)c(Cl)cc1C(=O)O
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2C(F)(F)F)c(Cl)cc1C(=O)O

Procedure:
To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid of Step A (3.12 g, 10 mmol) in N,N-dimethylformamide(100 mL) was added 2-trifluoromethyl phenyl boronic acid (5.70 g, 30 mmol) and potassium carbonate (12.73 g, 92 mmol). This mixture was purged with nitrogen and then treated with a catalytic amount of tetrakis(triphenylphosphine) palladium(0) (0.58 g, 0.5 mmol). The reaction was heated to reflux overnight, cooled, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to provide a nearly quantitative amount of the title acid which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][C:6]=1[C:15]1[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=1.[ClH:21]>C1COCC1>[Cl:21][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:15]1[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=1
Reactant: Cl
Reactant: CC(=O)Nc1ccc(OCCBr)c(-c2ccnn2C)c1
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(N)ccc1OCCCl
Temperature: 150 °C

Procedure:
A mixture of N-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (450 mg, 1.33 mmol), concentrated HCl (0.9 mL) in THF (4 mL) was heated with microwave irradiation at 150° C. for 30 minutes. The crude was concentrated in vacuo to give the title compound as a brown oil. Exact mass calculated for C12H14ClN2O 251.1, found 252.0 (MH+). This was used without purification in next step.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:16])[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)=[S:37])=[O:34])=[CH:28][CH:27]=1>C(#N)C>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:35][C:36](=[S:37])[NH:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][C:2]3[C:7]4=[C:8]([CH3:16])[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]4[N:5]=[CH:4][N:3]=3)=[CH:41][CH:40]=2)=[O:34])=[CH:30][CH:31]=1
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)cc1
Reactant: CCOC(=O)c1cn2ncnc(Cl)c2c1C
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CCOC(=O)c1cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3)c2c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a room temperature solution of ethyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (7.2 mg, 0.03 mmol) (for preparation see U.S. Pat. No. 6,670,357, the disclosure of which is herein incorporated by reference) and DABCO (7 mg, 0.06 mmol) in acetonitrile (0.5 mL) was added 1-(2-(4-fluorophenyl)acetyl)-3-(4-hydroxyphenyl)thiourea (0.5 mL, 0.05 mmol). The reaction was shaken at room temperature. After 30 min, LC/MS analysis indicated mostly product. The reaction was stirred at room temperature overnight. The mixture was evaporated to dryness. Purification by silica gel chromatography (eluting with 1% methanol/dichloromethane) provided the desired product contaminated with impurities. A second purification by silica gel chromatography (1–6% Ethyl acetate/dichloromethane) again did not remove all of the impurities. The resulting solid mixture was washed with methanol and dried to provide the title compound (6 mg, 39%) as a yellow solid. 1H NMR (CDCl3) δ 12.32 (s, 1H), 8.62 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.76 (m, 2H), 7.29 (m, 4H), 7.12 (m, 2H), 4.38 (q, 2H, J=7.1 Hz), 3.72 (s, 2H), 2.82 (s, 3H), 1.40 (t, 3H, J=7.1 Hz); MS(ESI+) m/z 508 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)#[CH:12]>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1C=CC=CC=1>[CH2:1]([N:8]1[C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:12][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1ccc(C=O)cc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O=Cc1ccc(-c2cnnn2Cc2ccccc2)cc1

Procedure:
Benzyl azide (0.200 g, 1.50 mmol), 4-ethynylbenzaldehyde (0.200 g, 1.54 mmol), Cp*RuCl(PPh3)2 (25 mg, 0.031 mmol). Solvent, benzene; reaction temperature, 80° C.; reaction time, 2 hours; yield, 0.32 g (81%). EI-MS: m/z 264 [M+1].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[S:11])[N:3]=1.[CH3:15][NH:16][CH3:17]>C(#N)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:16]([CH3:17])[CH3:15])[N:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[S:11])[N:5]=1
Reactant: CNC
Reactant: CCOC(=S)Cc1nc(Cl)cc(Cl)n1
Solvent: CC#N
Product: CCOC(=S)Cc1nc(Cl)cc(N(C)C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 4,6-dichloro-2-pyrimidinylthioacetate (6 g) in acetonitrile (25 ml) is treated with a 33% aqueous solution of dimethylamine (6.4 ml). The mixture is left to stand at room temperature for 1 hour, then is cooled for 2 hours at 0° C. The precipitate is filtered, washed with a small quantity of acetonitrile: 4.85 g of the desired product are obtained (III, 29).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]=1[O:12][CH3:13])[C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)(=O)C.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[C:10]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]=1[O:12][CH3:13]
Reactant: COC(=O)c1cc(F)c(OC)c(OCc2ccccc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(F)cc(CO)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
Methyl 3-fluoro-4-(methyloxy)-5-[(phenylmethyl)oxy]benzoate (3.54 g, 12.2 mmol.) was taken into anhydrous THF under a nitrogen atmosphere and the resulting solution was cooled to 0° C. A solution of lithium aluminum hydride (1.0M in THF, 20 mL) was slowly added and the solution was allowed to stir an additional 30 minutes at 0° C. Ethyl acetate (10 mL) was then slowly added followed by slow addition of 50% aqueous sodium hydroxide in portions until a granular precipitate was formed. Addition of anhydrous magnesium sulfate followed by filtration and washing the solid with ethyl ether then concentration of the combined organic layers gave an oily residue. Purification by silica gel flash chromatography using 2:1 hexanes:ethyl acetate as eluent provided {3-fluoro-4-(methyloxy)-5-[(phenylmethyl)oxy]phenyl}methanol (2.69 g, 84% yield) as a colorless oil after concentration of the pure fractions and drying in vacuo. GCMS for C15H15O3F: 262 (M+).
Reaction SMILES: COC(=O)[O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([F:14])=[CH:7][C:6]=1[CH3:15].B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[F:14][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([OH:4])=[C:6]([CH3:15])[CH:7]=1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(F)c([N+](=O)[O-])cc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
Carbonic acid 4-fluoro-2-methyl-5-nitro-phenyl ester methyl ester (1.8 g, 7.8 mmol) was dissolved in dichloromethane (100 ml) and cooled to 0° C. Boron tribromide (1 M in dichloromethane, 8 ml) was added. The mixture was allowed to warm to room temperature and was stirred overnight. To the solution was added 1N sodium hydroxide (25 ml) and the mixture was stirred vigorously for 1 hour. The layers were separated and the organic layer was dried over anhydrous sodium sulfate, and filtered and concentrated in vacuo to give 4-fluoro-2-methyl-5-nitro-phenol (1.083 g, 80.6%) as a red crystalline solid.
Reaction SMILES: Cl.[CH3:2][C@@:3]([C:7]([O:9][CH3:10])=[O:8])([CH2:5][OH:6])[NH2:4].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[Si:16]([O:6][CH2:5][C@@:3]([CH3:2])([C:7]([O:9][CH3:10])=[O:8])[NH2:4])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: COC(=O)[C@@](C)(N)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@](C)(N)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A mixture of (±)-methyl 2-methylserinate hydrochloride from Step A (14.4 g, 85.0 mmol) and imidazole (19.1 g, 280 mmol) in dry DMF (77 mL) was cooled to 0° C. and treated with tert-butyldimethylsilyl chloride (14.1 g, 93.0 mmol). The mixture was stirred at 0° C. for 25 min, and was then allowed to warm to ambient temperature and stirred for 18 h. Water (500 mL) was added and the mixture extracted with ether (4×150 mL). The combined organic extracts were washed successively with water and brine, dried (anhydrous Na2SO4), filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography, eluting with a gradient of EtOAc:CH2Cl2—0:100 to 100:0, afforded the title compound. MS: m/z=248 (M+1).
Reaction SMILES: [CH3:1][Li].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[N:5]1>C1COCC1>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[O:15])[CH3:1])=[N:5]1
Reactant: [Li]C
Reactant: Cn1nc(C(=O)O)c2ccccc21
Solvent: C1CCOC1
Product: CC(=O)c1nn(C)c2ccccc12

Procedure:
Methyl lithium (1.58M solution in ether; 13.8 ml) was added dropwise to a stirred, cold (-60°) solution of 1-methyl-1H-indazole-3-carboxylic acid (1.77 g) in dry THF (60 ml) under nitrogen and stirring was continued while warming to 0° over 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 ml), and the layers were separated. The aqueous layer was further extracted with dichloromethane (2×50 ml) and the combined organic layers were washed with brine (2×50 ml), dried and evaporated in vacuo. The residual solid (1.8 g) was purified by FCC eluting with System B (1:4) to give the title compound (1.3 g), m.p. 86°-88°.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:7]=1.FC(F)(F)C(O)=O.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:27])=[CH:24][C:23]=1[O:38][CH3:39].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][CH:30]2[CH2:31][CH2:32][N:33]([CH2:2][C:3]3[O:4][C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[N:6][N:7]=3)[CH2:34][CH2:35]2)=[O:27])=[CH:24][C:23]=1[O:38][CH3:39]
Reactant: COc1cc(C(=O)NCC2CCNCC2)ccc1Cl
Reactant: ClCc1nnc(-c2ccccc2)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCC2CCN(Cc3nnc(-c4ccccc4)o3)CC2)ccc1Cl
Temperature: 100 °C

Procedure:
2-(Chloromethyl)-5-phenyl-1,3,4-oxadiazole (31 mg, prepared according to the reported preparation in Natero, R.; et al. Synth. Commun. 2004, 34, 2523) was added to a solution of the compound prepared in Example 11 (60 mg) and diisopropylethylamine (0.083 mL) in N,N-dimethylformamide (0.8 mL). The solution was heated to 100° C. overnight. The reaction was cooled to room temperature, diluted with ethyl acetate and washed twice with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1, then ethyl acetate) to obtain the title compound (36 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=[O:13])[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1.[C:19](O)(=[O:21])[CH3:20]>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:21])[CH3:20])[C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=[O:13])[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1
Reactant: Nc1cc(F)cc2c1OCCC21SC(=O)NC1=O
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(F)cc2c1OCCC21SC(=O)NC1=O

Procedure:
61 mg of (±)-6-fluoro-8-amino-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione were heated to 50° C. for 90 minutes in a mixture of 1.2 ml of glacial acetic acid and 1.2 ml of acetic acid anhydride and the resulting mixture was subsequently concentrated to dryness in vacuo. After boiling up briefly with active carbon in methanolic solution, the residue was crystallized from methanol and yielded (±)-6-fluoro-8-acetamido-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione in the form of a light brownish material of melting point 278°-280° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.Cl>CN(C)C=O>[SH:7][C:4]1[S:3][C:2]([S:1][CH2:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[N:6][N:5]=1
Reactant: Sc1nnc(S)s1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CSc2nnc(S)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
To a mixture of 1.2 g of 2,5-dimercapto-1,3,4-thiadiazole, 1.1 g of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide was added 0.5 g of ethyl p-(bromomethyl)benzoate followed by stirring at room temperature for 3 hours. The reaction mixture was made acidic with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography followed by eluting with a solvent mixture of toluene-ethyl acetate (9:1). The thus obtained crystals were recrystallized from toluene-n-hexane to give 230 mg of ethyl p-[(5-mercapto-1,3,4-thiadiazol-2-yl)thiomethyl]benzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[CH:23]([CH:25]=O)=[O:24]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:25][CH:23]=[O:24]
Reactant: O=CC=O
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Product: CC1=C(CCON=CC=O)c2cc(F)ccc2/C1=C\c1ccncc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with glyoxal by the method of Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[S:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][C:7]=3[CH2:8][O:9][C:10]=2[CH:11]=1.C([Sn](CCCC)(CCCC)[C:23]([O:25]CC)=[CH2:24])CCC.[F-].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[S:14]1[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:23](=[O:25])[CH3:24])=[CH:11][C:10]=3[O:9][CH2:8][C:7]=2[CH:12]=[C:13]1[C:15](=[O:17])[CH3:16]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)c1cc2c(s1)-c1ccc(Br)cc1OC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)OCc1cc(C(C)=O)sc1-2
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
A solution of 1-(7-bromo-4H-thieno[3,2-c]chromen-2-yl)ethanone (1b) (14 g, 45.3 mmol) in 300 ml of anhydrous dioxane was degassed by passing nitrogen gas for 45 min. Tributyl(1-ethoxyvinyl)stannane (16.35 g, 45.3 mmol) was added to it followed by Pd(PPh3)4 (4.19 g, 3.62 mmol) and PdCl2(dppf)-CH2Cl2 adduct (2.65 g, 3.62 mmol) and the solution was heated at 90 OC for overnight. After cooling, the volume of dioxane was reduced, and a saturated solution of KF was added to it and stirred for 15 min., after which the mixture was passed through a pad of celite and washed with ethyl acetate. The combined filtrate was stirred with 4N HCl solution for 1 h and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to obtain the diacetyl compound (1c) (11.5 g, 68%). m/z 272.9 (M+H)+.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[H-].[Na+].Cl[C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1.O>O1CCCC1>[CH2:1]([O:4][C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[CH:2]=[CH2:3]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of allyl alcohol (650 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl )pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:21])[C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
To a solution of ethyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (100 mg, 0.317 mmol) in THF:MeOH:H2O (3:2:1; 6 mL) was added NaOH (25 mg, 0.634 mmol). The reaction mass was stirred at rt for 3 h. The reaction mass was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 14.10 (s, 1H), 8.14 (br t, 1H), 7.38-7.26 (m, 2H), 4.25 (d, J=5.4 Hz, 2H), 1.11 (s, 9H).
Reaction SMILES: [Cl-].[Zn+2:2].[Cl-].[Mg].[CH3:5][N:6]([CH3:11])[CH2:7][CH2:8][CH2:9]Cl>O1CCCC1>[CH3:5][N:6]([CH3:11])[CH2:7][CH2:8][CH2:9][Zn:2][CH2:9][CH2:8][CH2:7][N:6]([CH3:11])[CH3:5]
Reactant: [Zn+2]
Reactant: CN(C)CCCCl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(C)CCC[Zn]CCCN(C)C
Temperature: 70 °C

Procedure:
A solution of 38.2 g (0.28 mol) of zinc chloride in 100 ml of tetrahydrofuran is added dropwise at room temperature to a Grignard reagent prepared from 24.3 g (1.0 mol) of magnesium and 102.1 g (0.84 mol) of 3-di-methylaminopropyl chloride in 500 ml of tetrahydrofuran, and the mixture is then heated at 70° C. for 2 hours. After cooling, insoluble material is separated off by filtration, the solvent is removed and the residue is distilled in vacuo. Bis(3-dimethylaminopropyl)zinc is obtained as a crystalline solid having a melting point of 40° C. and a boiling point of 68° C./0.1 mbar.