Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:19](=[O:21])[NH2:20])[NH:11][C:10]=2[C:9]([Cl:22])=[CH:8][CH:7]=1.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:19](=[O:21])[NH2:20])[N:11]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:10]=2[C:9]([Cl:22])=[CH:8][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c3cccc(C(N)=O)c3c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 78 mg of [5-carbamoyl-1-chlorocarbazol-4-yl]oxyacetic acid methyl ester in 0.8 ml of dry dimethylformamide was added to 10 mg sodium hydride (60% in mineral oil) in 0.2 ml of dimethylformamide and stirred for 15 minutes. Benzyl bromide (0.031 ml) was then added and the reaction was stirred overnight. The reaction mixture was poured into water and acidified with 1 ml of 1 N HCl solution and extracted twice with ethyl acetate. The extracts were washed with water (3×) and then with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with methanol/0-2% in dichloromethane to afford 40 mg of the subtitle compound. ESIMS m/e 423 (M++1) 425 (M++3) NMR (300 MHz, CDCl3): δ 7.43-7.22 (m, 7H); 7.06 (d, J=7.3, 2H); 6.51 (d, J=8.6, 1H); 6.05 (s, 2H); 5.80 (br, 2H); 4.88 (s, 2H); 3.83 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[CH:14][C:15]([NH2:19])=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:27](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:28]>C(Cl)Cl>[N:19]([C:15]1[CH:14]=[N:13][C:12]2[C:17](=[CH:18][C:9]([CH3:8])=[CH:10][CH:11]=2)[N:16]=1)=[C:27]=[S:28]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1ccc2ncc(N)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2ncc(N=C=S)nc2c1
Yield: 46 %

Procedure:
A mixture of 7-methylquinoxalin-2-amine 2,2,2-trifluoroacetate (546 mg, 2 mmol) 78263-058-01, triethylamine (243 mg, 2.40 mmol), and 1,1′-thiocarbonyldipyridin-2(1H)-one (557 mg, 2.40 mmol) was stirred in 5 mL DCM for 2 h. The reaction was directly eluted on a 120 g silica gel cartridge with 0 to 25% EtOAc in hexane, 25 min, at 35 mL/min to afford 2-isothiocyanato-7-methylquinoxaline (185 mg, 0.919 mmol, 46% yield).
Reaction SMILES: [CH2:1]([O:3][NH:4][CH2:5][C:6]1[C:7]([F:29])=[C:8]([F:28])[C:9]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:10]([CH:18]=1)[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[CH3:2].[C:30](ON1C(=O)C2C=CC=CC=2N=N1)(=[O:32])[CH3:31]>C(O)(=O)C>[C:30]([N:4]([CH2:5][C:6]1[C:7]([F:29])=[C:8]([F:28])[C:9]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:10]([CH:18]=1)[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[O:3][CH2:1][CH3:2])(=[O:32])[CH3:31]
Reactant: CC(=O)On1nnc2ccccc2c1=O
Reactant: CCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Solvent: CC(=O)O
Product: CCON(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)C(C)=O
Yield: 71 %

Procedure:
The title compound was prepared by a procedure similar to that in Example 41. Namely, 5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide obtained in Example 17 was reacted with 4-oxo-4H-benzo[d][1,2,3]triazin-3-yl acetate prepared from acetic acid to give 5-[(acetyl-ethoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (19.3 mg, 71%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(C)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc([C@@H]2COc3cc(O)ccc3[C@@H]2c2ccc(OCCN3CCCC3)cc2)cc1

Procedure:
Thus (±)-cis-7-methoxy-3-(4-methylphenyl)-4-(4-(2-pyrrolidinoethoxy)phenyl)-chromane was de-methylated by heating with pyridine hydrochloride to give the racemic mixture, (±)-cis-7-hydroxy-3-(4-methylphenyl)-4-(4-(2-pyrrolidinoethoxy)-phenyl)chromane. The title compound was then separated from this racemic mixture by means of preparative chiral HPLC {Chiradex 5 μm, 250×25 mm column; flow=20 ml/min; 50% methanol, 50% buffer (0.2% aqueous triethylammonium acetate, pH 3.5) eluent, 220 nm UV detection}. The title compound was the more slowly eluted enantiomer, Rt=20-30 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[CH2:30][O:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:49]2[CH:61]=[CH:60][C:52]([CH2:53][N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[CH:51][CH:50]=2)O1.C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[CH2:30][O:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:49]3[CH:61]=[CH:60][C:52]([CH2:53][N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)=[CH:51][CH:50]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(COC2(c3ncc(-c4c(Cl)cnc5c4cc(I)n5S(=O)(=O)c4ccc(C)cc4)s3)COC2)cc1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COc1ccc(COC2(c3ncc(-c4c(Cl)cnc5c4cc(-c4ccc(CN6CCOCC6)cc4)n5S(=O)(=O)c4ccc(C)cc4)s3)COC2)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(3-(4-methoxybenzyloxy)oxetan-3-yl)thiazole (Example 11G) (200 mg, 0.282 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (120 mg, 0.395 mmol) in N,N-dimethylformamide (2.65 mL) was added saturated aqueous bicarbonate solution (0.883 mL) followed by bis(triphenylphosphine)palladium dichloride (13.88 mg, 0.020 mmol). The mixture was heated to 70° C. for 4 hours and was then quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 30% ethyl acetate in hexane, to afford the title compound. MS ESI(+) m/z 757.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][N:10]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:27]=[CH:26][C:20]([CH2:21][O:22][C:23](Cl)=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15].C(N(CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22][C:23](=[O:24])[NH:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])=[CH:26][CH:27]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCN=[N+]=[N-]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A solution of (2-azidoethyl)carbamic acid t-butyl ester (1.22 g, 6.55 mmol) in methanol (60 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (1.22 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered, and the filtrate concentrated under reduced pressure. To a solution of the obtained crude product in methylene chloride (60 ml) were added chloroformic acid p-nitrobenzyl ester (2.12 g, 9.8 mmol) and triethylamine (1.37 ml, 9.8 mmol) in an ice bath, and the reaction mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (3:1) as the eluant to afford (2-t-butoxycarbonylaminoethyl)carbamic acid p-nitrobenzyl ester (1.46 g, yield 66%) as a white solid.
Reaction SMILES: [C:1]1([C:7]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[CH:28]=[C:29]([CH:38]=[CH:39][C:40]=4[NH2:41])[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:54](Cl)(=[O:59])[CH2:55][CH2:56][CH2:57][CH3:58].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:48]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:27]4[CH:28]=[C:29]([CH:38]=[CH:39][C:40]=4[NH:41][C:54](=[O:59])[CH2:55][CH2:56][CH2:57][CH3:58])[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])=[CH:23][CH:24]=3)=[N:11][N:10]=[N:9]2)[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CCCCC(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1OCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCC(=O)Nc1ccc(C(=O)N2CCOCC2)cc1OCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound ([3]-(34)-587) (0.07 g) prepared in Example 38 and 4-dimethylaminopyridine (0.01 g) were dissolved in dry pyridine (1 ml). Valeryl chloride (0.043 g) was added dropwise by a syringe while cooling on ice. The mixture was stirred at room temperature for 2 hours, then, poured into water (20 ml), extracted with chloroform (10 ml) twice, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the compound ([3]-(35)-587') (0.08 g) as a light yellow solid.
Reaction SMILES: [C:1](/[N:3]=[C:4](\SC)/[NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)#[N:2].[NH2:16][NH2:17]>C(O)C>[NH2:2][C:1]1[N:3]=[C:4]([NH:5][C:6]2[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=2)[NH:17][N:16]=1
Reactant: NN
Reactant: CS/C(=N\C#N)Nc1cc(Cl)cc(Cl)c1
Solvent: CCO
Product: Nc1n[nH]c(Nc2cc(Cl)cc(Cl)c2)n1
Yield: 99 %

Procedure:
A solution of (Z)-methyl N′-cyano-N-(3,5-dichlorophenyl)carbamimidothioate (8 g, 30.8 mmol) and hydrazine (9.85 g, 9.65 ml, 308 mmol) in Ethanol (120 ml) was stirred at 70° C. for 3 h. It was concentrated to a small volume and water was added to give a suspension. The suspension was filtered, washed with water to give a white solid as desired product (7.44 g, 99% yield). MS +m/z: 244.0 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11]Cl)[S:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CN(C=O)C.C(Cl)Cl>[O:22]1[CH2:23][CH2:24][N:19]([CH2:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1csc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
2-Chloromethyl-thiazole-4-carboxylic acid ethyl ester (500 mg, 2.431 mmol) and potassium carbonate (504 mg, 3.65 mmol) were dissolved in dry DMF and morpholine (0.212 ml, 2.431 mmol) was added. The reaction mixture was stirred at RT overnight, diluted with DCM and washed with NaHCO3 and water. Organic phase was evaporated to dryness to yield the title compound (93%). 1H-NMR (400 MHz; DMSO-d6): δ 1.30 (t, 3H), 2.49-2.54 (m, 4H, overlap with DMSO), 3.58-3.63 (m, 4H), 3.84 (s, 2H), 4.29 (q, 2H), 8.47 (s, 1H). m/z [256.3+1].
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([OH:7])([CH3:6])[CH2:4][NH3+:5].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:9])([F:8])[C:3]([OH:7])([CH3:6])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]1=[O:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(O)(C[NH3+])C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(CN1C(=O)c2ccccc2C1=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture comprising 3,3,3-trifluoro-2-hydroxy-2-methyl-propyl-ammonium (0.9 g), phthalic anhydride (1.039 g) and DIPEA (2.188 ml) in chloroform (30 ml) was heated at 70° C. for 5 hours. After cooling to RT, the mixture was washed with water and passed through a phase separator. The organic phase was reduced to dryness. The crude product was purified by chromatography on silica, eluting in a 0% to 30% iso-hexane:EtOAc removed to give the title product; 1H NMR (400 MHz, Methanol-d4) δ 7.92 (2H, m), 7.85 (2H, m), 3.95 (2H, m), 1.36 (3H, s).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@H:49]([C:54]3[CH:59]=[CH:58][C:57](O)=[CH:56][CH:55]=3)[C:50]([O:52][CH3:53])=[O:51])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:26]([O:25][C:24]([NH:23][CH2:22][CH2:21][O:20][C:57]1[CH:58]=[CH:59][C:54]([C@@H:49]([NH:48][C:46]([O:45][CH2:44][CH:42]2[C:43]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[C:36]3[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:47])[C:50]([O:52][CH3:53])=[O:51])=[CH:55][CH:56]=1)=[O:30])([CH3:27])([CH3:29])[CH3:28]
Reactant: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(OCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
To a solution of 0.465 g (1.77 mmol) of triphenylphosphine in 10 mL of THF was added 0.286 g (1.77 mmol) of tert-butyl N-(2-hydroxyethyl)-carbamate followed by 0.476 g (1.18 mmol) of methyl(2R)-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}(4-hydroxyphenyl)ethanoate and 0.279 mL (1.77 mmol) of diethyl azodicarboxylate. The reaction was stirred overnight at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to give 0.383 g of methyl (2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl){[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethanoate as a white solid. Electrospray Mass Spec 547.2 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:13])[C:11]=1[OH:12])[C:6]([OH:8])=[O:7])=O.C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C.[F:27][C:28]([F:37])([F:36])/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>CS(C)=O.CC(C)=O>[CH2:34]([O:33][C:31]([C:30]1[CH:29]([C:28]([F:27])([F:36])[F:37])[O:12][C:11]2[C:3]([CH:1]=1)=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][C:10]=2[CH3:13])=[O:32])[CH3:35]
Reactant: Cc1cc(C(=O)O)cc(C=O)c1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2cc(C(=O)O)cc(C)c2OC1C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of 3-formyl-4-hydroxy-5-methylbenzoic acid (8.8 g, 48.89 mmole), K2CO3 (13.49 g, 97.78 mmole), triethylamine (19.79 g, 195.56 mmole), and ethyl 4,4,4-trifluorocrotonate (32.85 g, 195.56 mmole) in anhydrous DMSO (20.0 mL) was heated to 90° C. under a dry N2 atmosphere for 18 hrs. The mixture was then cooled, poured into 2.0 N HCl (100 ml), and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to give an oily solid. Redissolved in acetone to givea white precipitat, which was filtered and dried on high vacuum (7.2 g, 51%). GCMS m/z 330.0 (M+). 1H NMR (DMSO/400 MHz) 12.99 (s, 1H), 8.11 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 6.19 (q, 1H, J=7.0 Hz), 4.35 (m, 2H), 2.31 (s, 3H), 1.36 (m, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[Cl:22])[C:12]2[C:11](=[O:23])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:24])(=[O:3])[CH3:2].ClCCl.F[B-](F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34].CO>O>[C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[Cl:22])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:23][CH2:33][CH3:34])[NH:6][C:5]=1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC[O+](CC)CC
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1Cl)C(C(C)=O)=C(C)N2
Reaction time: 2 h

Procedure:
245 mg (0.721 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-3-chlorobenzonitrile are dissolved under an argon atmosphere in 15 ml of abs. dichloromethane, and 273 mg (1.442 mmol) of triethyloxonium tetrafluoroborate are added. After a reaction time of two hours at room temperature (reaction checked by HPLC), the mixture is mixed with 5 ml of methanol and 0.5 ml of water and stirred for a further 2 h. It is then diluted with 20 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 127 mg (47.9% of theory) of the title compound are obtained.
Reaction SMILES: O[CH:2]([C:11]1[CH:20]=[CH:19][C:18]2[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:9]=[O:10])[O:6][C:7]=1[CH3:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:8][C:7]1[O:6][C:5]([CH:9]=[O:10])=[CH:4][C:3]=1[CH2:2][C:11]1[CH:20]=[CH:19][C:18]2[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1
Reactant: Cc1oc(C=O)cc1C(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(C=O)cc1Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution containing 4-[hydroxy-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-5-methyl-2-furaldehyde (3.6 g, 11 mmol), triethylsilane (3.8 g, 33.1 mmol) and anhydrous methylene chloride (50 mL) was cooled to 0° C. To this mixture was added trifluoroacetic acid (˜1.3 g, 11.4 mmol) and the reaction was allowed to stir at RT for 16 hours. The reaction was quenched with saturated NaHCO3 and the organics were separated and dried over MgSO4. The resulting oil was used without further purification (the product appears to quickly decompose).
Reaction SMILES: [CH2:1]([C:5]1([C:18]([O:20][CH3:21])=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH:7]=[C:6]1[O:16]C)[CH2:2][CH2:3][CH3:4].I[Si](C)(C)C>C(#N)C>[CH2:1]([C:5]1([C:18]([O:20][CH3:21])=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C(=O)OC)C(OC)=CC(=O)c2ccccc21
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CCCCC1(C(=O)OC)C(=O)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of Example 1B (1 g, 3.5 mmol) in acetonitrile (5 mL) was added iodotrimethylsilane (TMSI) (0.7 mL, 5.2 mmol). The reaction solution was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. Column chromatography on silica (ethyl acetate) afforded the title compound as a white solid (0.88 g, 92%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.47 (m, 1H), 0.68 (t, J=7.35 Hz, 3H), 0.85 (dd, J=12.32, 7.17 Hz, 1H), 1.11 (m, 2H), 2.14 (m, 1H), 2.29 (m, 1H), 3.51 (s, 3H), 5.74 (m, 1H), 7.31 (m, 1H), 7.49 (m, 1H), 7.58 (t, J=7.17 Hz, 1H), 7.93 (d, J=7.35 Hz, 1H), 12.11 (s, 1H); MS(ESI) m/z 275.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:10]>C1(C)C=CC=CC=1>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: O=C(CN1CCOCC1)c1ccc(Br)cc1
Yield: 101.3 %

Procedure:
Morpholine (4.35 g) in dry toluene (8 ml) was stirred during the addition of aliquots of 2-bromo-1-(4-bromophenyl)ethanone (6.95 g) in dry toluene (70 ml). The resulting precipitate was removed by filtration and the filtrate evaporated to give the product (J. Amer. Chem. Soc., 1940, 62, 2882) as a pale yellow solid (7.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36].[H-].[Li+].[Cl:43][CH2:44][CH2:45][CH2:46]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:46][CH2:45][CH2:44][Cl:43])[CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36]
Reactant: ClCCCI
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1N(CCCCl)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.8 g, 1.33 mmol) prepared in example 55b was reacted with LiH (0.5 g, 62.5 mmol) and 1-chloro-3-iodo-propane (3.9 g, 19.1 mmol) in N,N-dimethyl-formamide (20 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(3-chloro-propyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white form (Yield: 0.43 g, 47.8%).