Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5](=[NH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:2]#[CH:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:23]([CH:25]([C:29](Cl)=[O:30])[C:26](Cl)=[O:27])[CH3:24]>C1COCC1>[CH2:23]([C:25]1[C:29](=[O:30])[N:4]([CH2:1][C:2]#[CH:3])[C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N:12][C:26]=1[OH:27])[CH3:24]
Reactant: C#CCNC(=N)c1ccccc1
Reactant: CCC(C(=O)Cl)C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCn1c(-c2ccccc2)nc(O)c(CC)c1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 93.6 %

Procedure:
To a cold (-78° C.) solution of N-propargylbenzamidine (5.50 g, 34.77 mmol) in 150 mL of THF was added sodium bis(trimethylsilyl)amide (36.51 mL, 36.51 mmol, 1.05 equiv, 1M solution in THF) over 20 minutes. The reaction mixture was stirred for 5 minutes at -78° C., followed by the addition of a cold (-78° C.) solution of ethylmalonyl dichloride (6.46 g, 38.25 mmol, 1.1 equiv.) in 150 mL of THF via a canula over 2 hours. After stirring for 30 minutes, the reaction mixture was quenched with 100 mL of water, warmed to room temperature, and diluted with 300 mL of ethyl acetate and 100 mL of water. The organic layer was successively washed with 200 mL of water and 200 mL of saturated sodium chloride, dried (MgSO4), filtered, and concentrated to give a solid. The crude mixture was azeotropically evaporated with 200 mL of toluene to remove residual hexamethyldisilazane, affording 8.28 g of 5-ethyl-6-hydroxy-2-phenyl-3-propargyl-4(3H)-pyrimidinone which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].Cl.Cl.[C:22]([O:26][N:27]=[C:28]1[CH:32]([CH2:33][NH2:34])[CH2:31][NH:30][CH2:29]1)([CH3:25])([CH3:24])[CH3:23].N12CCCN=C1CCCCC2.O>C(#N)C>[NH2:34][CH2:33][CH:32]1[CH2:31][N:30]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:29][C:28]1=[N:27][O:26][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)ON=C1CNCC1CN
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)ON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1CN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
141 mg (0.5 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid and 143 mg (0.55 mmole) of 4 -aminomethyl-pyrrolidin-3-one t-butyloxime dihydrochloride were thoroughly suspended in 2.5 ml of acetonitrile. Then, 230 mg (1.5 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene was slowly added dropwise thereto. The reaction mixture was stirred for 30 minutes at room temperature, and after adding 1 ml of water, was then vigorously stirred for 10 minutes and filtered. The filtered solid product was successively washed with acetonitrile-water (4:1 v/v, 2 ml) and acetonitrile (2 mlX2) and then with ether and dried to obtain 132 mg (Yield: 61%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:23][C:24]1[C:25]([C:38](O)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:29]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:25]([C:38]([NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:28][CH:29]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)n1
Reactant: Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4cccc(C(F)(F)F)c4)ncnc23)n1
Yield: 43.8 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-7, 50 mg, 0.164 mmol), 3-chloro-6-(pivalamidomethyl)picolinic acid (Intermediate-3, 85 mg, 0.314 mmol), oxalyl chloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (63 mg, 0.49 mmol) in CH2Cl2 (2 mL) to afford 40 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 11.62 (s, 1H), 10.14 (s, 1H), 8.94 (d, J=7.8 Hz, 1H), 8.77 (s, 1H), 8.32-8.27 (m, 4H), 8.11 (d, J=8.7 Hz, 1H), 7.75-7.64 (m, 2H), 7.51-7.46 (m, 2H), 4.49 (d, J=5.7 Hz, 2H), 1.17 (s, 9H); MS [M+H]+: 557.16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CC)[CH:5]=[CH:6][C:7]=1[Cl:8].C([Cl:29])(=O)CCCCCCCC>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([Cl:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCCCCCCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CCCCCCCCC(=O)Cl
Product: CCCCCCC(Cl)c1ccc(Cl)c(Cl)c1

Procedure:
3',4'-dichlorononanophenone, b.p. 155°-157° C./0.25 mmHg, from nonanoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[C:11]([OH:20])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O.CN(C=O)C.O.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:21])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[C:11]([O:20][CH3:22])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cc(O)cc2c1CCCC2=O
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(OCC(=O)OC(C)(C)C)c2c(c1)C(=O)CCC2
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a suspension of (3-hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (XXX, 78 mg, 0.27 mmol) and potassium carbonate (111 mg, 0.8 mmol) in acetone (4 mL) and DMF (2 mL) was added iodomethane (114 mg, 0.8 mmol) at room temperature under nitrogen. The resulting red-brown suspension was heated at reflux for 2 days. The reaction mixture was then cooled to room temperature and diluted with water (10 mL) and brine (10 mL). The resulting mixture was extracted with ethyl acetate (2×35 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by using ISCO (40 g) column chromatography (gradient elution with 5-40% ethyl acetate in hexanes) to obtain (3-methoxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (76 mg, 94%) as a light yellow solid: ES(+)-HRMS m/e calcd. for C17H22O5 (M+H)+307.1540, obsd. 307.1540.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH2:33])=[CH:27][CH:26]=1>>[C:25]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][NH:33][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)=[CH:29][CH:30]=1
Reactant: NCCc1ccc(-c2ccccc2)cc1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCCc3ccc(-c4ccccc4)cc3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(1,1′-biphenyl-4-yl)ethylamine gave the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][C:3]=1[O:17][CH3:18].[H-].[Na+].Br[CH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1.[Cl-].[NH4+]>CN(C)C=O.ClCCl.CCCCCC>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]2[CH2:22][C:23]2[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1cc2cc(-c3ccccc3)[nH]c2cc1F
Reactant: CCOC(=O)c1csc(CBr)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)c1csc(Cn2c(-c3ccccc3)cc3cc(OC)c(F)cc32)n1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 36.7 %

Procedure:
To a solution of 6-fluoro-5-methoxy-2-phenylindole (200 mg) in N,N-dimethylformamide (4.1 mL) was added sodium hydride (dispersed in liquid paraffin, minimum 55%, 54 mg) under cooling with ice, and the mixture was stirred at room temperature for 70 minutes. Then a solution of ethyl 2-bromomethylthiazole-4-carboxylate (249 mg) in N,N-dimethylformamide (0.2 mL) was added, and the mixture was stirred at 80° C. for 25 hours. The reaction mixture was allowed to cool to ambient temperature. A saturated aqueous ammonium chloride solution-water (2/1) were added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (125 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1(C)C=CC=CC=1.O[CH:19]1[O:24][CH2:23][CH:22]2[CH:20]1[CH:21]2[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(OCC)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1.O>[OH:24][CH2:23][CH:22]1[CH:20]([CH:19]=[CH2:11])[CH:21]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C1C2COC(O)C21
Reactant: Cc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: C=CC1C(CO)C1C(=O)OCC
Reaction time: 1 h
Yield: 188.4 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (5.2 g, 14.5 mmol) in anhydrous dioxane (75 mL) at room temperature under a nitrogen atmosphere, a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (24.4 mL, 12.2 mmol) was added. After 1 hour, the mixture was added via cannula to a solution ethyl (1RS,5SR,6RS)-2-hydroxy-3-oxabicyclo[3.1.0]-hexane-6-carboxylate (1.0 g, 2.62 mmol) in anhydrous dioxane (25 mL) under a nitrogen atmosphere and the reaction mixture was stirred for 1 hour. Then, the mixture was poured onto a 2:1 mixture of diethyl ether and water (300 mL) and the layers were separated. The aqueous layer was extracted with diethyl ether (2×100 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by column chromatography using ethyl acetate and hexane 1:2 as eluent to afford 840 mg (85% yield) of ethyl (1SR,2SR,3RS)-2-hydroxymethyl-3-vinylcyclopropane carboxylate.
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[C:9]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH:21]=O)=O.[CH3:23][NH:24][CH3:25].C([BH3-])#N.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1.CCO.CO.CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[C:6]([CH2:21][N:24]([CH3:25])[CH3:23])[NH:5]2)[CH3:20]
Reactant: CCOC(=O)Cc1c(Cl)ccc2c1cc(C=O)n2C(=O)OC
Reactant: CNC
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cc1c(Cl)ccc2[nH]c(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Chloro-4-ethoxycarbonylmethyl-2-formyl-indole-1-carboxylic acid methyl ester (350 mg, 1.08 mmol) is dissolved in dry THF (10 ml) under an atmosphere of argon, and dimethylamine (290 microL of a 5.6 M solution in EtOH, 1.62 mmol) is added at RT. The reaction mixture is stirred at RT for 18 hours. A solution of sodium cyanoborohydride (82 mg, 1.29 mmol) in methanol (3 ml) and acetic acid (310 microL, 5.40 mmol) is then added. Stirring is continued for 3 hours at RT. TLC analysis indicates complete conversion of the starting material. The reaction mixture is diluted with EtOAc and poured on water. The pH is made alkaline by the addition of a saturated aqueous solution of NaHCO3. The aqueous layer is extracted with EtOAc, and the combined organic layers are washed once with concentrated aqueous NaCl solution. After drying over Na2SO4, the solvent is removed and the residue is purified by FCC (CH2Cl2/EtOH/aq. NH3 90:9:1) to give the title compound. 1H NMR (DMSO, 400 MHz) δ 1.19 (t, J=6.6 Hz, 3H), 2.20 (s, 6H), 3.55 (s, 2H), 3.97 (s, 2H), 4.11 (q, J=6.6 Hz, 2H), 6.38 (s, 1H), 7.08 (d, J=9.0 Hz, 1H), 7.26 (d, J=9.0 Hz, 1H), 11.2 (br s, 1H); ES-MS: 293.2 [M+H]−.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[N:2].Cl.[NH2:19][OH:20].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[OH:20][NH:19][C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[NH:2]
Reactant: N#C[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
Part A. Benzyl (S)-2-cyanopyrrolidine-1-carboxylate (500 mg, 2.17 mmol) was dissolved in aqueous ethanol (3 mL) and water (1 mL). Hydroxylamine hydrochloride (152 mg, 2.17 mmol) and Na2CO3 (115 mg, 1.08 mmol) were added and the reaction mixture heated to 100° C. for 1 h. The ethanol was removed and the aqueous residue was extracted with dichloromethane (3×25 mL), dried over Na2SO4 decanted and concentrated yielding benzyl (S)-2-(N-hydroxycarbamimidoyl)pyrrolidine-1-carboxylate as a pale yellow gum (428 mg, 75% yield): HPLC (method 1) tR=1.40 min, Purity 76%; LCMS (method 4) tR=0.81 min, m/z 264 (M+H).
Reaction SMILES: [S:1]([Cl:3])Cl.[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:8]=[CH:9][C:10]=1[Cl:11].N1C=CC=CC=1>C(Cl)Cl>[Cl:3][S:1][N:12]([C:7]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([Cl:4])[CH:6]=1)[C:13]([N:15]([CH3:16])[CH3:17])=[O:14]
Reactant: ClSCl
Reactant: CN(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C(=O)N(SCl)c1ccc(Cl)c(Cl)c1

Procedure:
A 5.7-g (0.055 mol) sample of sulfur dichloride was added dropwise to a mixture of 11.7 g (0.05 mol) of N-(3,4-dichlorophenyl)-N',N'-dimethyl urea and 4.7 g (0.06 mol) pyridine in 50 ml methylene chloride cooled in an ice bath. After the completion of the addition, the pyridine hydrochloride was filtered. Hexane was added to precipitate additional pyridine hydrochloride, which was removed by filtration. Evaporation of the resulting filtrate gave the product as a clear yellow oil. The NMR spectrum showed an N',N'-dimethyl singlet at 3.0 ppm (relative to tetramethylsilane). Elemental analysis showed:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:10][CH:11](Br)[C:12]([O:14][CH2:15][CH3:16])=[O:13].CC(C)([O-])C.[K+]>CN(C)C=O>[Br:10][CH:11]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(Br)Br
Reactant: O=[N+]([O-])c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Br)c1ccc([N+](=O)[O-])cc1

Procedure:
Nitrobenzene was treated with ethyl dibromoacetate in dimethylformamide containing potassium tertiarybutoxide at -20° C. to give ethyl 2-bromo-2-(4-nitrophenyl)acetate (1.37 parts) which was dissolved in methanol (50 parts). To this methanol solution was added dropwise separately a solution of bromine (1.72 parts) in methanol (40 parts) and a solution of sodium methoxide (0.56 parts) in methanol (40 parts). The reaction mixture was poured into dilute aqueous hydrochloric acid solution and extracted with dichloromethane. The dichloromethane solution was evaporated to give methyl 2,2-dibromo-2-(4-nitrophenyl)acetate (1.44 parts, 50%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.BrC1C=CC=C2C=1NC(=O)C2.CC1C=CC=C2C=1NC(=O)C2.FC1C=C(F)C=C2C=1CC(=O)N2.[Cl:46]C1C=CC(Cl)=C2C=1CC(=O)N2.FC1C=C2C(=C(F)C=1)NC(=O)C2.C(C1C=C2C(=C(F)C=1)NC(=O)C2)CCC.C1(C2C=CC=C3C=2NC(=O)C3)CCCCC1.C1(C2C=CC=C3C=2NC(=O)C3)CC1>>[Cl:46][C:3]1[CH:2]=[C:10]2[C:6]([CH2:7][C:8](=[O:11])[NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C1Cc2cccc(F)c2N1
Reactant: O=C1Cc2c(Cl)ccc(Cl)c2N1
Agent: CCCCc1cc(F)c2c(c1)CC(=O)N2
Agent: Cc1cccc2c1NC(=O)C2
Agent: O=C1Cc2c(F)cc(F)cc2N1
Product: O=C1Cc2ccc(Cl)cc2N1

Procedure:
In an analogous manner 4- and 6-fluoro- and bromooxindoles are prepared, as well as 7-fluorooxindole, 7-bromooxindole, 7-methyloxindole, 4,6-difluorooxindole, 4,7-dichlorooxindole, 5,7-difluorooxindole, 5-n-butyl-7-fluorooxindole, 7-cyclohexyloxindole and 7-cyclopropyloxindole.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1>C(Cl)Cl>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:2][CH3:1])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN
Solvent: ClCCl
Product: CNC(=O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: To a mixture of 1250 ml of a 40% aqueous solution of methylamine and 1250 ml of methylene chloride, cooled in an ice bath, is added with stirring a solution of 500 g of 4-chlorobenzoylchloride in 625 ml of methylene chloride. After the addition (50 minutes), the mixture is stirred for an additional 2 hour. The white precipitate is filtered off and air dried and the methylene chloride layer of the filtrate is dried and evaporated to give the crude 4-chloro-N-methyl-benzamide, which, after crystallization from 1200 ml of methanol melts at 158°-161°; an additional amount of the product is recovered from the mother liquor, m.p. 158°-160°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[C:16]([NH2:17])[C:11]3=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34].O>CN(C=O)C>[NH2:17][C:16]1[C:11]2[C:12](=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:33]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=4[Cl:25])(=[O:35])=[O:34])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[NH:14][N:15]=1
Reactant: Nc1ccc(-c2ccc3c(N)n[nH]c3n2)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1n[nH]c2nc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.44 mmol) of 6-(4-aminophenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine are dissolved in 3 ml of anhydrous DMF. The solution is then degassed for 15 minutes with argon. 123.8 μl (89.9 mg, 0.89 mmol, 2 eq.) of triethylamine are subsequently added. The solution is once again degassed for 15 minutes. Finally, 0.109 g (0.444 mmol, 1 eq.) of 2,3-dichlorophenylsulphonyl chloride is added. The solution is stirred at ambient temperature under argon overnight. At the end of the reaction, 10 ml of water are added. A yellow-brown precipitate forms. The mixture is filtered. The solid is dried and purified on a column of 4 g of silica with an eluent gradient of 0 to 10% of methanol in dichloromethane. A beige solid is isolated (11 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][S:9][CH2:10][CH2:11][NH2:12]>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N:12][CH2:11][CH2:10][S:9][CH3:8]
Reactant: CSCCN
Reactant: O=Cc1ccc[nH]1
Product: CSCCN=Cc1ccc[nH]1
Yield: 98.7 %

Procedure:
Replicate the preparation of the ligand used in Ex. 7 except use 0.928 g (9.758 mmol) of the pyrrole-2-carbaldehyde and 0.999 mL (10.734 mmol, p=0.980 gcm−3) of 2-(methylthio)ethylamine instead of N1,N1-dimethylethane-1,2-diamine to give 1.62 g (98%) of N-((1H-pyrrol-2-yl)methylene)-2-(methylthio)ethanamine as a pale yellow oil, which is analytically pure by GC-MS & 1H-NMR: 1H NMR (400 MHz, CDCl3) δ 9.45 (s, br, 1H), 7.99 (s, 1H), 6.78 (s, 1H), 6.40 (d, J=1.9 Hz, 1H), 6.14 (s, 1H), 3.64 (t, J=6.9 Hz, 2H), 2.66 (t, J=6.9 Hz, 2H), 2.04 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:14]=[CH:13][C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)=[CH:18][CH:17]=1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1ccc(Cl)cc1
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(Cl)cc3)cc21

Procedure:
Prepared according to Procedure A from 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 4-chlorophenyl boronic acid. White solid: mp 255-257° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.7 (d, 2H, J=8.52 Hz), 7.55 (m, 2H), 7.5 (d, 2H, J=8.52 Hz), 6.96 (d, 1H, J=8.52 Hz), 1.7 (s, 6H); MS (ESI) m/z 288 ([M+H]+, 70%); Anal. Calc. For C16H14ClNO2: C, 66.79, H, 4.90, N, 4.87. Found: C, 66.34, H, 4.76, N, 4.75
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:16])[C:7]2=[O:27].Cl.[O:31]=[C:32]1[CH2:36][C:35]2([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:34][NH:33]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:1][C:2]1[C:3]([N:39]2[CH2:38][CH2:37][C:35]3([CH2:34][NH:33][C:32](=[O:31])[CH2:36]3)[CH2:41][CH2:40]2)=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:16])[C:7]2=[O:27]
Reactant: O=C1CC2(CCNCC2)CN1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C1CC2(CCN(c3c(F)cc4c(=O)c(C(=O)NCc5ccc(Cl)cc5Cl)cn(C5CC5)c4c3Cl)CC2)CN1

Procedure:
60 mg (0.13 mmol) of the compound of Example 70A and 37 mg (0.20 mmol) of 3-oxo-2,8-diazaspiro[4,5]decane hydrochloride (Example 13A) are stirred with 91 μl (0.52 mmol) of N,N-diisopropylethylamine in 2 ml of DMSO at 120° C. for 2 days. After cooling, the entire reaction mixture is separated by preparative HPLC (method 5). Concentration of the appropriate fractions on a rotary evaporator and drying under high vacuum give 20 mg (26% of theory) of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1.[Li]CCCC.CON(C)[C:32](=[O:45])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]1([CH3:44])[O:43][CH2:42][CH2:41][O:40]1.O>C1COCC1.CCCCCC>[CH3:44][C:39]1([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:32]([C:13]2[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[N:12]=2)=[O:45])[O:40][CH2:41][CH2:42][O:43]1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc3ccccc3c2)c1
Reactant: CON(C)C(=O)CCCCCCC1(C)OCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(CCCCCCC(=O)c2nc(-c3ccc4ccccc4c3)cn2COCC[Si](C)(C)C)OCCO1
Reaction time: 0.5 h

Procedure:
To a solution of E2 (1.0 eq.) in THF (0.1 M solution) at −78° C. was added a solution of n-BuLi (1.3 eq.) in hexane. The solution was stirred for 30 min and then a solution of N-methoxy-N-methyl-7-(2-methyl-1,3-dioxolan-2-yl)heptanamide (1.5 eq.) in THF was slowly added. The reaction mixture was stirred for 1 hr at −78° C. and then 1 hr at RT. Then water was added and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (MgSO4) and the solvent was removed under reduced pressure. The crude was purified by column chromatography on silica gel eluting with 20-50% EtOAc/petroleum ether to obtain E3 as yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.32 (1H, s), 7.96-7.81 (4H, m), 7.68 (1H, s) 7.53-7.42 (2H, m), 5.85 (2H, s), 3.92 (4H, s), 3.64 (2H, t, J=8.2 Hz), 3.26 (2H, t, J=8.2 Hz), 1.77 (2H, m), 1.69-1.36 (8H, m), 1.31 (3H, s), 0.97 (2H, t, J=8.2 Hz), 0.19 (9H, s). MS (ES) C30H42N2O4Si requires: 522, found: 523 (M+H)+.