Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:23])[C:5](=[O:22])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)C(F)(F)F)=[CH:11][CH:10]=1>CO>[CH3:23][N:4]([CH3:3])[C:5](=[O:22])[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: CN(C)C(=O)CCCc1ccc(NC(=O)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)CCCc1ccc(N)cc1
Reaction time: 14 h
Yield: 65.2 %

Procedure:
1 N NaOH solution (3 mL) was added to a solution of N,N-Dimethyl 4-[4-(2,2,2-Trifluoroacetylamino)phenyl]butanamide (Formula 46) (0.17 g, 0.55 mmol) in methanol (2 mL) at room temperature. The mixture was stirred for 14 hour. The mixture was partitioned with chloroform (25 mL) and water (25 mL). The organic layer was dried over MgSO4, and concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 9:1) to give N,N-Dimethyl 4-(4-aminophenyl)butanamide (Formula 47) (74 mg, 66%) as a white solid. 1H NMR δ 6.97 (d, 2H, J=8.3 Hz), 6.61 (d, 2H, J=8.3 Hz), 3.56 (br s, 2H), 2.92 (s, 6H), 2.56 (t, 2H, J=7.7 Hz), 2.28 (t, 2H, J=7.7 Hz), 1.91 (p, 2H, J=7.7 Hz).
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[CH2:6])([CH3:4])[CH3:3].[CH3:7][SiH:8]([Cl:10])[Cl:9]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.CCCCCC>[CH3:1][Si:2]([CH3:4])([CH3:3])[CH2:5][CH2:6][Si:8]([CH3:7])([Cl:10])[Cl:9]
Reactant: C=C[Si](C)(C)C
Reactant: C[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CCCCCC
Product: C[Si](C)(C)CC[Si](C)(Cl)Cl
Reaction time: 4 h
Yield: 67357.8 %

Procedure:
There was allowed 100 g (1.0 mmol) of trimethylsilyl ethene to react with 127 g (1.1 mol) of methyldichlorosilane in a 500-ml flask equipped with a dropping funnel, reflux condenser, stirrer and nitrogen gas introducing tube, by steps of placing 20 ml of a mixture of trimethylsilyl ethene and methyldichlorosilane and 0.0051 g (0.01 mmol) of chloroplatinic acid in the flask, adding dropwise the remaining mixture of trimethylsilyl ethene and methyldichlorosilane thereto over a period of 4 hours while stirring the reaction mixture, and continuing the stirring for another 1 hour to complete the reaction. Subsequently, 200 ml of hexane was added to the reaction mixture, and the catalyst precipitated was filtered off. The filtrate was condensed and vaccum-distlled. 145 g (yield: 75%) of (2-trimethylsilylethyl)methyldichlorosilane was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[N:12]2)[CH:5]=[C:6](I)[C:7]=1[O:8][CH3:9].[B:25]1(B2OC(C)(C)CC(C)O2)[O:30]C(C)(C)CC(C)[O:26]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+]>O1CCOCC1>[CH2:23]([O:22][C:20]([C:14]1[CH:13]=[N:12][N:11]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([O:8][CH3:9])=[C:6]([B:25]([OH:30])[OH:26])[CH:5]=2)[C:15]=1[C:16]([F:19])([F:18])[F:17])=[O:21])[CH3:24]
Reactant: CC1CC(C)(C)OB(B2OC(C)CC(C)(C)O2)O1
Reactant: CCOC(=O)c1cnn(-c2cc(F)c(OC)c(I)c2)c1C(F)(F)F
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2cc(F)c(OC)c(B(O)O)c2)c1C(F)(F)F

Procedure:
Ethyl 1-(3-fluoro-5-iodo-4-methoxyphenyl)-5-(trifluoromethyl)-1h-pyrazole-4-carboxylate (340 mg, 0.742 mmol), bis(hexyleneglycolato)diboron (283 mg, 1.113 mmol), tricyclohexylphosphine (62.4 mg, 0.223 mmol), potassium acetate (182 mg, 1.855 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (121 mg, 0.148 mmol) and 1,4-dioxane (10 mL) were sealed in a microwave vessel and subject to microwave irradiation at 140° C. for a total of 2 hrs (1+1). The crude mixture was combined with the reaction crude from an identical probe reaction (32 mg scale). Volatiles were removed under reduced pressure. The resulting crude mixture was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 100 g cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 40%). Related fractions were pooled and evaporated to afford a brown oil as a mixture of the titled compound and the de-iodinated reduced by-product (step B). LCMS calc.=376.09. found=377.18 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.C1C=CC=CC=1.Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[S:30]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C(=S)N2CCNCC2)cc(OC)c1OC
Yield: 61.5 %

Procedure:
A mixture of 1-(3,4,5-trimethoxybenzoyl)piperazine (2.0 g), a Lawesson reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide] (2.9 g) and benzene (20 ml) is heated for 30 minutes under reflux. 1N HCl (100 ml) and ethyl acetate are added to the reaction mixture. The mixture is shaken. The aqueous layer is separated, and treated with an aqueous solution of sodium hydroxide to make the system alkalline, followed by extraction with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is recrystallized from methylene chloride to give 1-(3,4,5-trimethoxythiobenzoyl)piperazine as pale yellow crystals (1.3 g), m.p. 116°-118° C.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:15][C:16]([CH2:21]Br)([CH2:19]Br)[CH2:17][OH:18]>C(O)C>[C:4]1([CH3:3])[CH:5]=[CH:6][C:7]([S:10]([N:13]2[CH2:21][C:16]3([CH2:19][O:18][CH2:17]3)[CH2:15]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: OCC(CBr)(CBr)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CC3(COC3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of KOH (4.98 g, 0.089 mol) and 4-methylbenzenesulfonamide (5.7 g, 0.033 mol) in 90 ml of ethanol, 3-bromo-2,2-bis(bromomethyl)propan-1-ol (9 g, 0.0277 mol) was added at room temperature and the reaction mixture was heated to reflux for 45 h. The solvent was removed by evaporation, 75 ml of 1 M KOH were added and the white suspension was left to stir for another 2 h at room temperature. The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give 4.87 g 6-toluene-4-sulfonyl-2-oxa-6-azaspiro[3.3]heptane (69%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.70-7.68 (m, 2H), 7.36-7.34 (m, 2H), 4.58 (s, 4H), 3.90 (s, 4H), 2.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)C1CC1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(C1CC1)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
(5-Chloro-benzo[1,3]-dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (100 mg, 0.29 mmol) and DIEA (0.15 mL, 0.88 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Cyclopropanecarbonyl chloride (0.03 mL, 0.35 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 68 (42 mg, 35% yield) as a white fluffy solid. LC-MS (M+H=411, obsd.=411).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>C(Cl)(Cl)Cl>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C:33]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[C:17]([CH3:23])[CH:18]=1)=[O:34]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)cc3C)c2cc1OC
Yield: 79 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methyl-aniline (50 mg) was dissolved in chloroform (3 ml), and 2,4-difluorophenyl isocyanate (23 μl) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration and was washed to give 59 mg (yield 79%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][CH2:27][C:28]1[C:29]([NH2:43])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[CH3:25]>>[NH2:43][C:29]1[N:30]=[CH:31][C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:33][C:28]=1[CH2:27][O:26][CH2:24][CH3:25]
Reactant: CCOCc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCOCc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1N

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-ethoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (Stage 166.1.1) to give the title compound as a white solid. (HPLC: tR 2.17 min (Method A); M+H=444 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.13 (s, 1H), 8.08-8.06 (m, 1H), 8.05-8.01 (m, 1H), 7.86-7.82 (m, 1H), 7.49-7.47 (m, 1H), 7.44-7.42 (m, 1H), 6.02 (s, br, 2H), 4.37 (s, 2H), 3.92 (s, 3H), 3.57 (s, 3H), 3.51 (q, 2H), 1.95 (s, 3H), 1.18 (t, 3H))
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].C([O-])(=O)C.[Na+].N[C@H](C(O)=O)CS.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>C(O)C.O>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]2[NH:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][S:6]2)=[CH:26][CH:25]=1
Reactant: N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: COc1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(C2N[C@H](C(=O)O)CS2)cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with L-cysteine hydrochloride monohydrate (500.0 g, 2.85 mol), sodium acetate (260.0 g, 3.17 mol) and water (4 L). The mixture was stirred until all of the L-cysteine dissolved. A solution of 4-methoxybenzaldehyde (426.0 g, 3.13 mol) in ethanol (3.5 L) was prepared and added to the reaction dropwise such that the internal reaction temperature was kept below 30° C. The reaction went from a clear solution to a thick white slurry during the addition of the 4-methoxybenzaldehyde solution. After 30 minutes, ethanol (3.5 L) was added to the reaction and the slurry thickened. Stirring was continued for 1 hour and then the solid was isolated by filtration, and the solid was washed with additional ethanol. The solid was dried in a vacuum oven at 50° C. over 48 hours to afford the title compound (610 g, 90%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13](=[CH2:16])[C:14]#[N:15]>C(OCC)C>[CH2:1]([N:8]([CH2:9][CH2:10][OH:11])[CH2:16][CH:13]([Cl:12])[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCNCc1ccccc1
Reactant: C=C(Cl)C#N
Solvent: CCOCC
Product: N#CC(Cl)CN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
2-(benzylamino)ethanol 2a (5 g, 0.03 mol) and 2-chloro-propenenitrile (3 g, 0.03 mol) were dissolved in 50 mL of anhydrous ethyl ether in an ice-water bath, heated to room temperature and stirred for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 3-(benzyl(2-hydroxyethyl)amino)-2-chloro-propanenitrile 2b (7 g) as a red oil liquid, which was used in the next step without further furification.
Reaction SMILES: [F:1][CH:2]1[CH2:7][C:6]([N+:14]([O-])=O)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4]([CH3:17])[C:3]1=[O:18]>C1COCC1.[Ni]>[NH2:14][C:6]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][N:4]([CH3:17])[C:3](=[O:18])[CH:2]([F:1])[CH2:7]1
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CC(F)C1=O
Agent: [Ni]
Solvent: C1CCOC1
Product: CN1CC(N)(c2ccccc2)CC(F)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 55 mg (0.218 mmol) rac-3-fluoro-1-methyl-5-nitro-5-phenyl-piperidin-2-one in 1.5 ml THF at 0° C. was added 100 ul Raney Nickel (50% in water). The mixture was stirred under a hydrogen atmosphere at 0° C. for 2 hours. The mixture was filtered and the catalyst was washed with THF. The filtrate was concentrated in vacuo to provide 48 mg (99%) of the title compound as a light yellow solid. MS (m/e): 223.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)([O-:3])=[O:2].[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]=1[OH:27])([CH3:16])([CH3:15])[CH3:14]>>[C:23]([C:19]1[CH:20]=[C:21]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[N+:10]([O-:12])=[O:11])[CH:22]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:18]=1[OH:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc(C(C)(C)C)c1O
Reaction time: 2 h
Yield: 61.5 %

Procedure:
Example I was repeated except that 122 mg (0.73 mmol) of 1,3-dinitrobenzene and 100 mg (0.48 mmol) of 2,6-di-t-butylphenol were used, and the reaction was conducted for two hours. The process afforded 110 mg (61% yield) of crystalline 2,6-di-t-butyl-4-(2',4'-dinitrophenyl)phenol.
Reaction SMILES: C(OC([N:8]1[C@@H:13]([CH2:14][CH2:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:10](=[O:28])[CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[Cl:27][C:23]1[CH:22]=[C:21]([N:11]2[CH2:12][C@H:13]([CH2:14][CH2:15][S:16]([CH2:19][CH3:20])(=[O:17])=[O:18])[NH:8][CH2:9][C:10]2=[O:28])[CH:26]=[CH:25][CH:24]=1
Reactant: CCS(=O)(=O)CC[C@H]1CN(c2cccc(Cl)c2)C(=O)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)CC[C@H]1CN(c2cccc(Cl)c2)C(=O)CN1
Reaction time: 0.5 h

Procedure:
Through a solution of the Boc-protected piperazinone from Step H (1.75 g, 4.06 mmol) in 20 mL of EtOAc at 0° C. was bubbled anhydrous HCl gas. The saturated solution was stirred for 30 minutes, then concentrated in vacuo to provide the hydrochloride of title compound as a white powder. This material was suspended in EtOAc and treated with dilute aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc, and the combined organic mixture was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting titled amine was reconcentrated from toluene to provide the title compound suitable for use in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[ClH:13].[CH3:14][O:15][CH2:16][CH2:17][OH:18]>>[ClH:13].[CH3:14][O:15][CH2:16][CH2:17][O:18][C:6](=[NH:7])[C:5]1[CH:8]=[CH:9][C:2]([NH2:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COCCO
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Product: COCCOC(=N)c1ccc(N)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
100 g of 4-amino-3-nitrobenzonitrile are suspended in 500 ml of 2-methoxyethanol. Gaseous hydrochloric acid is introduced, the temperature of the solution is allowed to rise to 70° C. in the course of the introduction, and the solution is maintained at this temperature by cooling until it decreases by itself. Finally, the solution is cooled to 0°-5° C., saturated with gaseous hydrochloric acid and allowed to stand overnight. The precipitate is then filtered off with suction, washed with isopropanol and dried over KOH in a desiccator.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]=1[CH3:25])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([Li])[CH2:27][CH2:28]C.IC(C)C>O1CCCC1>[C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N:16]([CH:27]([CH3:28])[CH3:26])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]=1[CH3:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(Nc2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)cc1
Reactant: [Li]CCCC
Solvent: CC(C)I
Solvent: C1CCOC1
Product: COc1ccc(N(c2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)C(C)C)cc1
Yield: 8.9 %

Procedure:
Following general procedure L and using 7-t-butyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 53, 0.13 g, 0.38 mmol), 1.6M solution of n-butyllithium in hexanes (0.5 mL, 0.8 mmol) and 2-iodopropane (0.5 mL, 5 mmol) in 2 mL of anhydrous tetrahydrofuran, the title compound (0.013 g, 8.9%) was obtained as a brown oil after separation from recovered 7-t-butyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 53, 0.07 g) by preparative normal phase HPLC using 4% ethyl acetate in hexanes as the mobile phase. 1H NMR (300 MHz, C6D6): δ 6.82 (d, 2H, J=9.1 Hz), 6.75 (s, 1H), 6.56 (d, 2H, J=9.1 Hz), 4.09(heptet, 1H, J=6.5 Hz), 3.89 (s, 2H), 3.40(s, 3H), 2.40 (s, 3H), 1.68 (s, 9H), 1.10-1.25(m, 3H), 0.99-1.10(m, 3H), 0.99 (s, 6H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:29][CH2:28]2)=[CH:23][CH:22]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:30][C:31]#[N:32].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:9]2[C:10](=[CH:11][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:13][CH:14]=2)[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[N:32][C:31]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCOc1ccc(NCc2ccccc2)c(C(=O)c2ccc(C3CC3)cc2)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C3CC3)cc1)nc(=O)n2Cc1ccccc1

Procedure:
A solution of 460 mg (1.21 mmol) of (2-benzylamino-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)-methanone (step E) and 118 mg (1.81 mmol) sodium cyanate in 20 ml glacial acetic acid is stirred at rt for 8 h. Then the mixture is diluted with water and ethyl acetate. The layers are separated and the organic phase is washed with water and bicarbonate solution. Chromatography (dichloromethane/MeOH) of the crude product affords a yellow foam. m.p. 112-113° C.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3S(C2C=CC=CC=2)(=O)=O)=[N:5][N:4]=1.[NH2:35][CH2:36][CH2:37][OH:38].[OH-].[Na+].Cl>C(#N)C.CS(C)=O.CO.C(O)(C)C>[NH:21]1[C:22]2[C:18](=[C:17]([C:15]3[CH:14]=[C:13]4[C:9]([CH:10]=[N:11][NH:12]4)=[C:8]([C:6]4[O:7][C:3]([CH2:2][NH:35][CH2:36][CH2:37][OH:38])=[N:4][N:5]=4)[CH:16]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: NCCO
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CS(C)=O
Solvent: CC#N
Product: OCCNCc1nnc(-c2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)o1
Temperature: 100 °C
Reaction time: 20 h
Yield: 14.5 %

Procedure:
4-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (100 mg, 0.184 mmol) in acetonitrile (2 ml) was treated with 2-aminoethanol (0.055 ml, 0.918 mmol) and heated in a microwave at 100° C. for 30 mins. The acetonitrile supernatant was pipetted off, and the solid washed with further acetonitrile (5 ml). The solid was dissolved in methanol and DMSO (1:1, 3 ml) and loaded onto a 2 g SCX cartridge. Methanol was eluted, then 2M ammonia in ethanol. Basic fractions were blown to dryness to give a brown solid. The fully-protected intermediate was treated with isopropanol (1.000 ml) followed by 2M aqueous sodium hydroxide (1.001 ml, 2.002 mmol) and stirred for 20 h at 20° C. The solution was neutralised by addition of 2M hydrochloric acid, then blown to dryness to give a brown solid. This was transferred into a small vial, and treated with DMSO/MeOH (1:1, 1 ml) then filtered and purified on MDAP (Method E). The appropriate fraction was blown to dryness to give the title compound as a beige solid (10 mg).
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[C:21](Cl)(=[O:23])[CH3:22]>CCCCCC.C1COCC1.CCOCC.[Cl-].[Zn+2].[Cl-]>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:19])([F:20])[C:15]([F:16])([F:17])[F:18])=[CH:12][C:13]=1[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1C(C)=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
7.4 ml of BuLi at 2.5M in hexane are added, at −70° C., to a solution of 3.5 g of 1-methoxy-4-pentafluoroethylbenzene in 50 ml of anhydrous THF. The medium is stirred for 30 minutes at −70° C. and then for 45 minutes at 0° C. 15.5 ml of a 1M solution of zinc chloride in ether are then added. After stirring for 10 minutes at 0° C., 1.33 ml of acetyl chloride are added. The medium is then deoxygenated with nitrogen and 332 mg of benzyl(chloro)bis(triphenylphosphine)palladium in 5 ml of anhydrous THF are introduced. The medium is stirred for 2 hours 30 minutes at 0° C. and then for 72 hours at RT. The medium is poured onto 2.5M HCl solution and then extracted with ether. The organic phase is washed with 5% NaHCO3 in water, with water and then with saturated NaCl solution. After drying over MgSO4 and evaporation, the crude product is purifed by flash chromatography on silica to give 2.25 g of a white solid. m.p.=47° C.