Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:19][NH2:20])=[C:13]([CH2:17][NH2:18])[CH:14]=2)[CH2:9]1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[C:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)#[N:22]>N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([N:4]([CH:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH2:17][NH:18][S:29]([C:26]3[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:28][CH:27]=3)(=[O:31])=[O:30])=[C:12]([CH2:19][NH:20][S:29]([C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[CH:11]=2)[CH2:16]1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1Cc2cc(CN)c(CN)cc2C1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCN(CCC)C1Cc2cc(CNS(=O)(=O)c3ccc(C#N)cc3)c(CNS(=O)(=O)c3ccc(C#N)cc3)cc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-(N,N-dipropylamino)-5,6-bis(aminomethyl)indane 52 (0.276 g, 1.00 mmol) in pyridine (4.0 ml) was cooled in ice, and 4-cyanobenzenesulfonyl chloride (0.61 g, 3.0 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with 10% sodium carbonate solution and extracted three times with ethyl acetate. The combined extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave a dark oil. Purification by flash chromatography (230-400 mesh silica gel, 60-80% ethyl acetate/hexane) gave the title compound (54) as an oil. The compound was dissolved in ethyl acetate and excess ethereal hydrochloric acid was added. The mixture was diluted with diethylether and filtered. The precipitate was washed with diethylether and dried under vacuum giving the hydrochloride salt of 54 as a tan solid (0.143 g).
Reaction SMILES: CS(C)=O.O=C1CCC(=O)N1OC(=O)CCC(NC[CH:20]1[O:24][C:23]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]([N:32](CC)[C:33](=O)[C:34](F)(F)F)[CH3:31])=[CH:28][C:22]=2[O:21]1)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>[CH3:34][CH2:33][NH:32][CH:30]([CH2:29][C:27]1[CH:26]=[CH:25][C:23]2[O:24][CH2:20][O:21][C:22]=2[CH:28]=1)[CH3:31]
Reactant: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)ON1C(=O)CCC1=O)O2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCNC(C)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 500 mg of bovine serum albumin (BSA) in 6.7 mL of 50 mM potassium phosphate (pH 7.5) was cooled in an ice-bath. To the solution was added 8.5 mL of DMSO dropwise, and the reaction mixture was maintained below room temperature. To the protein solution was added a solution of 12 mg (0.022 mmol) of 2L in 1.5 mL of anhydrous DMF dropwise. The reaction mixture was allowed to stir at room temperature 48 hours. The resulting conjugate was placed in a dialysis tube (10,000 MW cut-off) and was dialyzed in 1 L of 70% DMSO in 50 mM potassium phosphate (pH 7.5, 3 changes, at least 3 hours each), 1 L of 50% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 30% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 10% DMSO in 50 mM potassium phosphate (at least 3 hours) at room temperature. The trifluoroacetamido group of the conjugate was deprotected by dialysis of the resulting conjugate against 10% ammonium hydroxide for 3 days (1 L each for approximately 24 hours each), followed by 6 changes with 50 mM potassium phosphate (pH 7.5) at 4° C. (1 L each). The protein concentration was determined to be 7.12 mg/mL using BioRad Coomassie blue protein assay (Bradford, M., Anal. Biochem. 72:248, 1976). A total of 45 mL of the conjugate was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:19][C:20]([C@@H:22](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:23]([OH:34])([CH2:31][CH2:32][OH:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:52](OC(=O)C)(=[O:54])[CH3:53].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[C:52]([O:33][CH2:32][CH2:31][C@:23]([OH:34])([C@@H:22]([C:20](=[O:21])[NH:19][C@H:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=1)/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])(=[O:54])[CH3:53]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OCC)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)OC(C)(C)C)C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-ethoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (3.22 g, 4.51 mmol) was dissolved in dichloromethane (64 mL), and the mixture was then cooled to 0° C. in an ice bath. Acetic anhydride (1.07 mL, 11.3 mmol), triethylamine (0.63 mL, 4.52 mmol), and dimethylaminopyridine (55.1 mg, 0.451 mmol) were added in this order, and the mixture was then stirred at 0° C. for 1.5 hours. The mixture was quenched with water (46 mL), and then extracted with dichloromethane (46 mL). The organic layer was washed with a saturated aqueous solution (33 mL) of sodium chloride, then dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 2.65 g (3.51 mmol, 78% yield) of No. 5328456.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[S:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[C:10]=2[O:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:5]=[CH:6][CH:7]=1>[OH-].[Li+].CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[S:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[C:10]=2[O:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1csc(Cc2cccc(Cl)c2)c1OCCO[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCOc1c(C(=O)O)csc1Cc1cccc(Cl)c1
Reaction time: 18 h
Yield: 42.5 %

Procedure:
Methyl 5-[(3-chlorophenyl)methyl]-4-{2-[(1,1-dimethylethyl)dimethylsilyl]oxyethoxy}thiophene-3-carboxylate (10.2 g) was dissolved in a mixture of 1M lithium hydroxide (50 ml), methanol (50 ml) and tetrahydrofuran (150 ml) and stirred for 18 hr. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and 2M hydrochloric acid. The organic layer was collected, dried and filtered. t-Butyl-dimethylsilyl chloride (7 g) and imidazole (3.1 g) were added to the solution and the mixture was stirred for 72 hours. The reaction mixture was concentrated and the residue was dissolved in methanol. Potassium carbonate (5 g) was added to the solution and the suspension was vigorously stirred for 3 minutes, then filtered and concentrated. The residue was dissolved in ethyl acetate, washed with 2M hydrochloric acid, dried, filtered and concentrated. The residue was purified by chromatography, eluting with 10:1:1 isohexane:ethyl acetate:acetic acid, to give the sub-title compound (4.2 g).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[CH:8]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl>O1CCCC1>[CH:8]1([C:14]([OH:15])=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N#CCC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C#N)=C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a 60 ml tetrahydrofuran solution of 3.96 g (0.06 mol) of malononitrile, 4.8 g (60% in oil, 0.12 mol) of sodium hydride was added at 0° C. in four divided portions, and the mixture was stirred for 30 minutes at 0° C. Then, cyclohexanecarboxylic acid chloride was added dropwise, and the mixture was stirred for 30 minutes at room temperature. Then, 150 ml of 1M hydrochloric acid was slowly added, and the mixture was extracted with ethyl acetate. Then, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Recrystallization of the residue from diisopropyl ether gave 8.16 g (77%) of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:27][CH2:28][CH2:29][NH:30][C:31](=[O:34])[CH2:32][CH3:33])=[N:10][CH:11]=[C:12]([C:14]([N:16]3[C@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][O:18]C3(C)C)=[O:15])[CH:13]=2)=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O.C(=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:27][CH2:28][CH2:29][NH:30][C:31](=[O:34])[CH2:32][CH3:33])=[N:10][CH:11]=[C:12]([CH:13]=2)[C:14]([NH:16][C@@H:20]([CH2:19][OH:18])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:15])=[CH:6][CH:7]=1
Reactant: CCC(=O)NCCOc1ncc(C(=O)N2[C@H](CC(C)C)COC2(C)C)cc1-c1ccc(Cl)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(=O)NCCOc1ncc(C(=O)N[C@@H](CO)CC(C)C)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
N-{2-[3-(4-Chloro-phenyl)-5-((R)-4-isobutyl-2,2-dimethyl-oxazolidine-3-carbonyl)-pyridin-2-yloxy]-ethyl}-propionamide (82 mg, 0.16 mmol) was dissolved in methanol (0.35 mL). To the solution was added camphorsulfonic acid (1.6 mg, 0.007 mmol) and the reaction mixture was stirred for 1 h at RT. The mixture was poured into water, sodiumbicarbonate was added and the mixture extracted with ethyl acetate. Organic phases were pooled, the solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (dichloromethane/methanol gradient) to yield 55 mg of the title compound as a white solid, MS (ISP) 448.3 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[O:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:11][CH2:12]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(N2CCOCC2)cc1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 4-fluorobenzonitrile and morpholine.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][O:28]C)[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].ClCCl.B(Br)(Br)Br.O>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][OH:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCCc1nc(CO)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
4′-{[4-Butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.0 g) was dissolved in dichloromethane (20 mL), and 1.0 M boron tribromide dichloromethane solution (1.0 M, 16 mL) was added at 0° C. After stirring at room temperature for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate and diethyl ether to give the title compound (1.7 g, 86%) as a colorless solid.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:22])=[CH:3]\[C:4]([O:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[CH:12][CH:11]=1)=[O:5].[N+:23]([C:26]1[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=1)[CH:29]=[C:30]([C:38]([CH3:40])=O)[C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32])([O-:25])=[O:24]>C1(C)C=CC=CC=1>[CH3:22][C:2]1[NH:1][C:38]([CH3:40])=[C:30]([C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32])[CH:29]([C:28]2[CH:41]=[CH:42][CH:43]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)[C:3]=1[C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)=[O:5]
Reactant: C/C(N)=C/C(=O)OCC=Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: COCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: Cc1ccccc1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
297 mg (1 mM) of 3-[4-(1-imidazolylmethyl)phenyl]-2-propen-1-yl 3-aminocrotonate and 293 mg (1 mM) of 2-methoxyethyl 2-(3-nitrobenzylidene)acetoacetate were dissolved in 5 ml of toluene and refluxed for six hours. After cooling, the crystals produced were filtered off and recrystallized from methanol whereby the captioned compound was obtained. The yield was 502 mg (87.6%).
Reaction SMILES: [C:1]([CH2:6][NH:7][C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11])([O:3][CH2:4][CH3:5])=[O:2].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[NH2:11][C:10]1[C:9]2[C:8](=[CH:15][C:14]([C:16]([F:18])([F:17])[F:19])=[CH:13][CH:12]=2)[NH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CNc1cc(C(F)(F)F)ccc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2cc(C(F)(F)F)ccc2c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
Dissolve 2-(Carbethoxy)methylamino-4-trifluoromethylbenzonitrile (2.34 g, 8.6 mmol) in tetrahydrofuran (40 mL) and add dropwise with stirring to a solution of potassium tert-butoxide (9.46 mL of a 1M tetrahydrofuran solution) under a nitrogen atmosphere at 0° C. The reaction was allowed to warm to room temperature. After 3 hour, dilute with ethyl acetate, rinse with water, saturated sodium chloride, dry magnesium sulfate, filter and concentrate in vacuo. Purify the residue by flash chromatography to yield the 3-amino-2-carbethoxy-6-trifluoromethylindole (1.22 g, 52%); mp 204°-210° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:26][CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[F:22])=[CH:7][CH:8]=3)=[N:13][O:14][C:15]=2[CH:20]=1
Reactant: Fc1ccc2c(-c3ccc(OCCCBr)cc3)noc2c1
Reactant: NCc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCCNCc4ccccc4F)cc3)noc2c1

Procedure:
The title compound is prepared from a mixture of 3-[4-(3-bromo-propoxy)-phenyl]-6-fluoro-benzo[d]isoxazole, 2-fluorobenzylamine, potassium carbonate, potassium iodide and 4% aqueous acetonitrile essentially as described above in Example 13. Purity by LC/MS=94%, [M+H]+=395.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27]([O-:29])=O)=[O:16])=[CH:13][CH:12]=2)=[CH:3][CH2:2]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].Cl.[NH2:40][OH:41]>CO.C[O-].[Na+]>[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27]([NH:40][OH:41])=[O:29])=[O:16])=[CH:13][CH:12]=2)=[CH:3][CH2:2]1
Reactant: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)[O-])c1ccc(C2=CCOc3ccccc32)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)NO)c1ccc(C2=CCOc3ccccc32)cc1
Reaction time: 1 h
Yield: 32 %

Procedure:
(5R,7S,8R)-8-{[4-(2H-chromen-4-yl)benzoyl]amino}-1-oxaspiro[4.4]nonane-7-carboxylate from reaction (34e) (0.10 g, 0.23 mmol) was dissolved in a solution of hydroxylamine hydrochloride, methanol and sodium methoxide, (2 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 1 h, made neutral with TFA, concentrated and purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient, to give the title compound (0.032 g, 32%) as a white solid. MS found: (M−H)+=433.
Reaction SMILES: [NH2:1][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[CH3:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=O.O>ClCCl>[CH3:7][C:8]([CH3:13])([CH3:12])[CH2:9]/[CH:10]=[N:1]/[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)CN
Reactant: CC(C)(C)CC=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C/C=N/C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of (aminomethyl)trimethylsilane (Fluka) (1.03 g, 10 mmol) in dichloromethane (20 mL) was added 3,3-dimethyl-butyraldehyde (Aldrich) (1.0 g, 10 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give [3,3-dimethyl-but-(E)-ylidene]-trimethylsilanylmethyl-amine as a colorless oil (1.8 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14](Cl)(Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)(Cl)Cl.Cl>C1(C)C(C)=CC=CC=1>[ClH:13].[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:14](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: ClC(Cl)(Cl)c1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1ccc(N=C(Nc2ccc(C(=O)OCC)cc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To a stirred suspension of ethyl 4-aminobenzoate (165.0 g; 1.0 mole) in xylene (465 mL) was added α,α,α-trichlorotoluene (100.7 g; 0.52 mole). The mixture was allowed to reflux for 18 h, then was cooled to 0° C. and filtered. The resultant precipitate was washed with ice-cold xylene (2×70 mL), triturated with hot toluene and dried to yield the salt (89.8 g; 39.7%) as white crystals: mp 214.0°-215.5° C. 1H-NMR (CDCl3) 8.0-6.9 (m, 14H), 4.3 (q, 4H, J=7 Hz), 1.4 (t, 6H, J=7 Hz); IR (CHCl3) 1715, 1600; MS (m/e) 416 (M+ -HCl), 252 (base).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([OH:30])[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([O:30][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 12 h
Yield: 118.3 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.07 g, 6.81 mmol) and 3-(1-cyano-1-methylethyl)-N-(4-ethyl-3-hydroxyphenyl)benzamide (2.0 g, 6.48 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.34 g, 9.72 mmol), and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed with water (150 mL), 5% aqueous sodium hydrogen carbonate solution (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→30/70). The obtained solution was concentrated under reduced pressure to give the title compound (3.3 g, quantitative) as a yellow amorphous substance.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[F:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:16][CH2:15][N:14]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2=CCNCC2)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2=CCN(S(C)(=O)=O)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
4-(3-Fluoro-4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride salt (462.00 mg, 1.90 mmol) is suspended in dichloromethane (10 mL). Triethylamine (479.58 mg, 660.57 μL, 4.74 mmol) and methanesulfonyl chloride (260.59 mg, 176.07 μL, 2.27 mmol) are added and the reaction is capped and stirred at room temperature for 16 h. The reaction is partitioned between dichloromethane and water. The aqueous layer is extracted with dichloromethane. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness. The crude material is purified by chromatography using a 5 g silica gel cartridge eluting with dichloromethane to provide 349 mg of the title compound as a white solid. MS (m/z) 286 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:14]([C:17]1[CH:18]([C:35]2[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=2)[NH:19][C:20](=[S:34])[N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:22]=1[CH3:23])(=[O:16])[CH3:15]>CN(C=O)C>[C:14]([C:17]1[CH:18]([C:35]2[CH:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=2)[N:19]=[C:20]([S:34][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[C:22]=1[CH3:23])(=[O:16])[CH3:15]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCSC1=NC(c2ccc(C#N)cc2)C(C(C)=O)=C(C)N1c1cccc(C(F)(F)F)c1
Reaction time: 15 h

Procedure:
To a solution of 2-bromoethyl acetate (37.6 mg, 0.23 mmol) in 500 μl DMF are added potassium carbonate (82.9 mg, 0.6 mmol) and 4-{5-acetyl-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}benzonitrile (Example 1; 62.3 mg, 0.15 mmol). The reaction mixture is shaken for 15 hours, filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; flow rate: 25 ml/min; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.