Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[C:8]([O:10]C)=O.[CH3:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].Cl>CCCCCC.O1CCCC1>[CH3:18][O:17][C:13]1[CH:12]=[C:7]([C:8](=[O:10])[CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:6]=[C:5]([O:4][CH3:3])[C:14]=1[O:15][CH3:16]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)CC(=O)C(C)(C)C)cc(OC)c1OC
Reaction time: 5 h
Yield: 73.6 %

Procedure:
In a 200 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 3.0 gm (75 mmol) of 60% sodium hydride, 10 gm (44.3 mmol) of methyl 3,4,5-trimethoxybenzoate, and 80 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and refluxed with heating while 5.3 gm (53.2 mmol) of pinacolone was added dropwise. Refluxing under heat was continued for 5 hours. After cooling the reaction mixture, 45 ml of 2N hydrochloric acid was added, the mixture was extracted twice with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Hexane was added to the crude product and insoluble substances were filtered off. The filtrate was concentrated by evaporation, and recrystallization afforded 9.6 gm of the target compound as colorless needles (yield: 74%).
Reaction SMILES: C[Al](C)C.Cl.[CH3:6][NH:7][CH3:8].C([O:11][C:12](=O)[CH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][N:19]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])C>C1C=CC=CC=1>[CH3:6][N:7]([CH3:8])[C:12](=[O:11])[CH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][N:19]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: CNC
Reactant: CCOC(=O)CCc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Agent: C[Al](C)C
Agent: Cl
Solvent: c1ccccc1
Product: CN(C)C(=O)CCc1cccc2c1ccn2S(=O)(=O)c1ccccc1

Procedure:
Trimethylaluminium (1.4 ml, 2M solution in hexanes) was added to a suspension of dimethylamine hydrochloride (228 mg, 2.8 mmol) in 10 ml benzene. The reaction was allowed to stir for 1 h before dropwise addition of a solution of 3-[1-(benzenesulphonyl)-1H-indol-4-yl]propionic acid ethyl ester (0.5 g, 1.4 mmol) in benzene (10 ml). The reaction was heated at reflux for 18 h, allowed to cool and then quenched by addition of HCl (2N, 5 ml). The reaction was partitioned between H2O-EtOAc. The organic phase was washed with brine, dried (MgSO4), and concentrated to give the title compound as an oil which crystallised (527 mg, 100%); δH (CDCl3, 250 MHz), 2.63 (2H, t, J=7.5 Hz), 2.79 (2H, br s), 3.16 (2H, t, J=8.5 Hz), 6.74 (1H, d, J=0.7 Hz), 6.08 (1H, d, J=7.5 Hz), 7.21-7.27 (1H, m), 7.41-7.58 (4H, m), 7.84-7.90 (3H, m).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[N:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:12][C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:15]([CH3:16])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)=[O:31])=[CH:26][CH:25]=2)=[N:22][CH:23]=1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cn2)cc1
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(Cl)cn4)cc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-(5-chloro-2-pyridyl)benzenecarboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:14][C@@H:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([OH:18])=O)[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1([C:27]#[N:28])[CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C.BrC1C=CC=CC=1[Li].CC(C)CC(N)C12OCC(C)(CO1)CO2.N[C@H](C(O)=O)CC(C)C>>[C:27]([C:24]1([NH:23][C:16](=[O:18])[C@@H:15]([NH:14][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:26][CH2:25]1)#[N:28]
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1nccs1)C(=O)O
Reactant: N#CC1(N)CC1
Agent: CC(C)CC(N)C12OCC(C)(CO1)CO2
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CC(C)NC(C)C
Product: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1nccs1)C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared by the coupling of (2S)-2-{(S)-[(4-bromophenyl)-thiazol-2-yl-methyl]-amino}-4-methylpentanoic acid with 1-aminocyclopropanecarbonitrile in the presence of HATU and diisopropylamine, in similar manner to that described for the preparation of Example 34. The synthesis of (2S)-2-{(S)-[(4-bromophenyl)-thiazol-2-yl-methyl]-amino}-4-methylpentanoic acid was accomplished via addition of bromophenyllithium (generated in situ from 1,4-dibromobenzene and n-butyllithium) to the imine condensation product between thiazole 2-carboxyaldehyde and 3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butylamine (L-leucine OBO ester, prepared according to the method described for Example 34), followed by ortho ester deprotection.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C@@H:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])[C:8](=O)[CH2:9][C@H:5]12)[CH3:3].C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH3:74][N:75]([CH3:97])[C:76]([C:78]1[CH:83]=[CH:82][C:81]([Sn](CCCC)(CCCC)CCCC)=[CH:80][CH:79]=1)=[O:77]>C(#N)C.CN1CCCC1=O.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[CH3:74][N:75]([CH3:97])[C:76]([C:78]1[CH:83]=[CH:82][C:81]([C:8]2[CH2:9][C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:24](=[O:25])[N:6]3[C:7]=2[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])=[CH:80][CH:79]=1)=[O:77]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)N(C)C)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3ccc(C(=O)N(C)C)cc3)C[C@H]12
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, to a solution of 128 mg (0.368 mmol) of 4-nitrobenzyl (3R,5R,6S)-6-((1R)-1-hydroxyethyl) -2-oxo-1-carbapenam-3-carboxylate in acetonitrile (3 ml) was added 0.065 ml (0.37 mmol) of diisopropylethylamine followed by 0.062 ml (0.37 mmol) of trifluoromethanesulfonic anhydride at -45° C., and the mixture was stirred for 30 minutes. To the mixture was added ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. After the extract was dried over anhydrous magnesium sulfate, the solvent was removed. To the crude triflate was added 113 mg (0.83 mmol) of zinc chloride, 5.3 mg (0.0091 mmol) of bis(benzylideneacetone)palladium(0) and 4.4 mg (0.019 mmol) of tri(2-furyl)phosphine. Under a nitrogen atmosphere, to the mixture was added a solution of 191 mg (0.4436 mmol) of (4-dimethylaminocarbonylphenyl)tri-n-butyltin in N-methylpyrrolidinone (6 ml), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added ethyl acetate, and the organic layer was washed with water (50 ml×2) followed by saturated aqueous sodium chloride. After the extract was dried over anhydrous magnesium sulfate, the solvent was removed. The residue was purified by silica gel column chromatography (elution with 3% methanol-chloroform) to give 9.lmg (yield: 27.9%) of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:13]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1nccnc1N1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2ccnc(N3CCOCC3)c2n1
Temperature: 0 °C

Procedure:
To a solution of compound 1b (6.00 g, 33.3 mmol) in DMF (100 mL) was added ethyl 3-bromo-2-oxopropanoate (8.00 g, 41.0 mmol) dropwise with stirring. The resulting solution was stirred at rt overnight. The reaction mixture was cooled to 0° C. The solids were collected by filtration and washed with Et2O (3×100 mL). Compound 1c was obtained as a white solid (8.40 g, 81% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C13H16N4O3: 276.1 (M+H). found: 276.3.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.Cl[C:57]1[CH:62]=[C:61]([O:63][CH:64]([CH3:66])[CH3:65])[C:60]([N+:67]([O-:69])=[O:68])=[CH:59][C:58]=1[CH3:70]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:49][N:50]1[CH2:55][CH2:54][N:53]([C:57]2[CH:62]=[C:61]([O:63][CH:64]([CH3:65])[CH3:66])[C:60]([N+:67]([O-:69])=[O:68])=[CH:59][C:58]=2[CH3:70])[CH2:52][CH2:51]1
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1Cl
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1N1CCN(C)CC1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
24.9 g of caesium carbonate, 745 mg of palladium acetate, 2.88 g of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and 4.89 g of 1-methylpiperazine are added to a solution of 7.62 g of 1-chloro-2-methyl-4-nitro-5-(propan-2-yloxy)benzene (prepared according to WO2008/073687, p. 31) in 380 ml of dioxane under argon. The mixture is refluxed for 5.5 h, and then cooled to ambient temperature. The mixture is combined with the crude product of one and the same reaction carried out on 1.89 g of 1-chloro-2-methyl-4-nitro-5-(propan-2-yloxy)benzene under the same conditions. The mixture is concentrated under vacuum and the residue is taken up with 100 ml of water, 200 ml of ethyl acetate and a little methanol. The mixture is filtered on Clarcel and the aqueous phase is extracted twice with 100 ml of ethyl acetate. The combined organic phases are washed with 100 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum. The crude product is purified on 340 g of silica, elution being carried out with 0-100% of acetone in dichloromethane, so as to obtain 5.60 g of 1-methyl-4-[2-methyl-4-nitro-5-(propan-2-yloxy)phenyl]piperazine in the form of a black solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:23][C@H:24]([C:29]([OH:31])=O)[CH2:25][CH2:26][CH2:27][CH3:28])([O:18]C(C)(C)C)=O.[CH2:32]([NH:39][CH2:40]C(OCC)=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:32]([N:39]1[CH2:40][C:16](=[O:18])[NH:23][C@@H:24]([CH2:25][CH2:26][CH2:27][CH3:28])[C:29]1=[O:31])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The title compound was prepared according to the procedure described by John S. Kiely and Stephen R. Priebe in Organic Preparations and Procedures Int., 22 (6), 761-768 (1990). Thus dicyclohexylcarbodiimide (9.33 g, 45.2 mmol) in methylene chloride (0.5M) was added to methylene chloride (250 mL). This solution was cooled to 0° C. under nitrogen and Boc-L-norleucine (10.5 g, 45.2 mmol) was added. The resulting slurry was stirred for 5 min, and then ethyl N-benzylglycinate (8.72 g, 45.2 mmol) was added. The reaction was stirred for 2 h at 0° C., then at 20° C. overnight. The precipitate was removed by filtration, and hydrogen chloride gas bubbled through the methylene chloride solution for 2-4 h, until the reaction was shown to be complete by tic. The solvent was removed in vacuo, and the residue partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate solution (42 mL). The organic phase was washed with saturated sodium chloride, dryed over magnesium sulfate, filtered and evaporated. The crude diketopiperazine was triturated with hexane to give the title compound as a white powder. 1HNMR (300 MHz, CDCl3) δ 7.24-7.40 (5H, m), 6.22 (1H, br s), 4.07 (1H, dt, J=3, 6 Hz), 3.87 (1H, d, J=17 Hz), 3.80 (1H, d, J=17 Hz), 1.88 (2H, m), 1.35 (4H, m), 0.91 (3H, t, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH2:24]([NH2:26])[CH3:25]>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][NH:26][CH2:24][CH3:25])[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CCN
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Product: CCNCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with ethylamine using an analogous method to that described for the equivalent step in Example 1 to give N-(3-chloro-2-fluorophenyl)-6-[(ethylamino)methyl]-7-methoxyquinazolin-4-amine; 1H NMR Spectrum: (DMSO-d6) 1.09 (t, 3H); 2.63 (q, 2H); 3.83 (s, 2H); 3.97 (s, 3H); 7.20 (s, 1H); 7.27 (t, 1H); 7.50 (m, 2H); 8.33 (s, 1H); 8.43 (s, 1H); 9.77 (s, 1H); Mass Spectrum: (M+H)+ 361.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[K].[CH2:26]([NH:33][S:34](=[O:37])(=[O:36])[NH2:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O.CO>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:35][S:34](=[O:36])(=[O:37])[NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: NS(=O)(=O)NCc1ccccc1
Reactant: Clc1ccc(-c2c(Cl)ncnc2Cl)cc1
Agent: [K]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: O=S(=O)(NCc1ccccc1)Nc1ncnc(Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.1 %

Procedure:
To 4,6-dichloro-5-(4-chloro-phenyl)-pyrimidine (Referential Example 9) (2.59 g) dissolved in DMSO (14 ml) was added di-isopropyl-ethyl-amine (1.8 ml) followed by the addition of benzyl sulfamic acid amide potassium salt (2.25 g) [prepared from the product described in Referential Example 22 and potassium tert.-butylate in methanol followed by the evaporation of the solvent]. The mixture was stirred for 24 h at rt then poured onto water (300 ml) and diethylether (120 ml) was added and the solution was stirred for 30 min. The layers were separated and the water layer was acidified with solid citric acid (pH=3) and cooled to 0° C. for 1 h. The precipitated product was filtered off, washed with water and recrystallized from methanol to give benzyl sulfamic acid-[6-chloro-5-(p-chloro-phenyl)-4-pyrimidinyl]-amide (1.8 g). tR=4.94 min (LC); [M+H]+410.90 (ES+);
Reaction SMILES: C(O)C.[C-:4]#[N:5].[Na+].CS(O[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]([CH3:20])[CH3:19])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl.C(Cl)Cl>[CH3:19][N:18]([CH3:20])[CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[C:4]#[N:5]
Reactant: CN(C)C1CCCCC1OS(C)(=O)=O
Reactant: [C-]#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CN(C)C1CCCCC1C#N

Procedure:
To 200 mL of 80% aqueous ethanol add 10 g (0.2 mol) of sodium cyanide and 22.1 (0.1 mol) of 2-(dimethylamino)-cyclohexanol methanesulfonate. Reflux the reaction and monitor by thin-layer chromatography. Upon completion add in HCl until gas evolution ceases. Remove solvent in vacuo and add saturated aqueous sodium carbonate (ph=11) and 100 mL of methylene chloride. Separate the layers and dry the organic phase over Na2SO4. Filter the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([OH:18])[CH:9]2[CH2:10][CH:5]3[CH2:6][C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.Cl[O-].[Na+]>C1COCC1.C(O)(=O)C.O>[C:12]1([C:7]23[CH2:6][CH:5]4[CH2:4][C:3]([C:2](=[O:18])[CH3:1])([CH2:11]2)[CH:9]([CH2:10]4)[CH2:8]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(O)C2CC3CC1CC(c1ccccc1)(C3)C2
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)C12CC3CC1CC(c1ccccc1)(C3)C2
Temperature: 25 °C

Procedure:
A solution of 2-methyl-5-phenyladamantan-2-ol (300 g) in THF (710 ml) and acetic acid (160 ml) was added at 0° C. to a solution (8.3%, 3330 ml) of sodium hypochloride in water. After addition of n-tetrabutylammonium iodide (25.6 g), the mixture was heated to 25° C. within 90 minutes. After full conversion and phase separation, the organic phase was washed repeatedly with water. After full concentration of the organic phase, the residue was taken up in methanol (525 ml). Potassium hydroxide (82 g) was added and the mixture was stirred at room temperature. After adding tert-butyl methyl ether, the mixture was washed repeatedly with water. The organic solution was clarified with activated carbon and concentrated fully under reduced pressure. This gave 1-(2-phenylhexahydro-2,5-methanopentalen-3a-yl)ethanone (320 g) as an oil.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].Cl.C(OCC)(=O)C>N1C=CC=CC=1>[C:15]([O:10][C:9]1[CH:11]=[CH:12][C:4](/[CH:3]=[CH:2]/[C:1]([OH:14])=[O:13])=[CH:5][C:6]=1[O:7][CH3:8])(=[O:17])[CH3:16]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)O)ccc1OC(C)=O
Reaction time: 24 h
Yield: 84.7 %

Procedure:
To a solution of ferulic acid (5 g, 25.75 mmoles) in pyridine (75 ml) cooled to 0° C. and sheltered from light, acetic anhydride (13.14 g, 128.7 mmoles) is added in small aliquots. When the addition is ended the temperature is let reach the room value maintaining the solution under magnetic stirring for 24 hours. HCl 18.5% (160 ml) is added up to pH 2, one extracts with ethyl acetate and the organic phase is anhydrified and the solvent is evaporated at a reduced pressure. 5.15 g of trans-3-[4-acetyloxy-3-methoxyphenyl]-2-propenoic acid are obtained as a white solid. M.p. 199-205° C. Yield 85%.
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[CH:9](=[N:11][OH:12])[CH3:10].[C:13]([C:15]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:26][CH:27]=2)[CH:18]=[CH:17][N:16]=1)#[CH:14].O>CN(C=O)C>[CH3:10][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[N:26][CH:27]=3)[CH:18]=[CH:17][N:16]=2)[O:12][N:11]=1
Reactant: CC=NO
Reactant: C#Cc1cc(Oc2ccc(NC(=O)OC(C)(C)C)nc2)ccn1
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2cc(Oc3ccc(NC(=O)OC(C)(C)C)nc3)ccn2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A solution of NCS (0.36 g, 2.70 mmol) in DMF (2 mL) was treated with acetaldoxime (0.16 g, 2.70 mmol), stirred at RT for 0.5 h, added to a solution of tert-butyl (5-((2-ethynylpyridin-4-yl)oxy)pyridin-2-yl)carbamate (0.28 g, 0.90 mmol) and TEA (2 mL) in DMF (2 mL) and heated at 60° C. for 2 h. The mixture was treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford tert-butyl (5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamate (250 mg, 75%). MS (ESI) m/z: 369.1 (M+H+).
Reaction SMILES: CN(C)CCN(C)C.[Li][CH:10]([CH2:12][CH3:13])[CH3:11].[CH3:14][O:15][C:16]1C=C[C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C(I)C>C1COCC1>[CH2:12]([C:10]1[CH:11]=[C:16]([O:15][CH3:14])[CH:17]=[CH:18][C:19]=1[C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[CH3:13]
Reactant: [Li]C(C)CC
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cc(OC)ccc1C(=O)N(CC)CC
Temperature: -78 °C
Reaction time: 1.17 h

Procedure:
To a solution of tetramethylethylenediamine (50.3 mL) in THF (800 mL) at -78° C. was added sec-BuLi (308 mL, 1.08M), followed by 4-methoxy-N,N-diethylbenzamide, (62.2 g). The mixture was stirred at -78° C. for 70 minutes, then ethyliodide (26.63 g, 333 mmol) was added over 35 minutes. The reaction mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was quenched with saturated NH4Cl (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a kugelrohr distillation at 190°-210° C. under high vacuum to afford 58.1 g of 2-ethyl-4-methoxy-N,N-diethylbenzamide.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([OH:6])=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[N:29]=[CH:28][C:27]([C:39]#[N:40])=[C:26]2[NH:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([Cl:49])[CH:43]=1>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][C:4]([NH:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[N:33]1[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1)[N:29]=[CH:28][C:27]([C:39]#[N:40])=[C:26]2[NH:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([Cl:49])[CH:43]=1)=[O:6]
Reactant: N#Cc1cnc2cc(N3CCOCC3)c(N)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: O=C(O)CCCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#Cc1cnc2cc(N3CCOCC3)c(NC(=O)CCCl)cc2c1Nc1ccc(F)c(Cl)c1
Reaction time: 20 h
Yield: 77.8 %

Procedure:
To a stirred solution of 3-chloropropionic acid (0.65 g, 6.0 mmol)in 3 ml of DCM at 0° was added DCC (0.41 g, 2.0 mmol). After 15 m the mixture was warmed to 25°, recooled to 0°, and treated with 6-amino-4-(3-chloro-4-fluroanilino)-7-(4-morpholinyl)-3-quinolinecarbonitrile (0.40 g, 1.0 mmol) followed by 1 ml DCM rinse. The resulting mixture was stirred at 25° for 20 h, diluted with DCM, and stirred with aqueous sodium bicarbonate. The mixture was filtered to remove dicyclohexyl urea. The organic layer of the filtrate was washed with water, dried, and concentrated. The residue was passed as a solution in DCM onto a pad of silica gel. The product was eluted with 25:25:2:1 DCM-EtOAc-MeOH-TEA and concentrated to give 0.38 g amorphous solid; ms 488.1(M+H)+.