Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.[NH3:19]>CO>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C@H:5]1[C:3](=[O:2])[NH2:19])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N
Reactant: COC(=O)[C@@H]1CCN1C(=O)OCc1ccccc1
Solvent: CO
Product: NC(=O)[C@@H]1CCN1C(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
A mixture of (S)-azetidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (2.5 g) and 7 M ammonia in MeOH (10 ml) was stood at it for 18 h in a sealed vessel. The RM was then evaporated to give the title compound as a white solid which was used without further purification. MS: M+H 235.1 and M−H 233.1.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:48][CH2:47][S:46](=[O:50])(=[O:49])[CH2:45][CH2:44]1>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([N:43]3[CH2:48][CH2:47][S:46](=[O:50])(=[O:49])[CH2:45][CH2:44]3)=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: O=S1(=O)CCNCC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)N4CCS(=O)(=O)CC4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and thiomorpholine 1,1-dioxide
Reaction SMILES: [F:1][C:2]1([F:19])[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:6]2)[NH:4][CH2:3]1.CC1N([C:26]([CH2:28][C:29]#[N:30])=[O:27])N=C(C)C=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:19][C:2]1([F:1])[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:6]2)[N:4]([C:26](=[O:27])[CH2:28][C:29]#[N:30])[CH2:3]1
Reactant: FC1(F)CNC12CCN(c1ncnc3[nH]ccc13)C2
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N1CC(F)(F)C12CCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 1.25 h
Yield: 83.1 %

Procedure:
An optically-active compound of 4-(3,3-difluoro-1,6-diazaspiro[3,4]oct-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (170 mg) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (209 mg), N,N-diisopropylethylamine (117 μl) and 1,4-dioxane (3.4 ml), and the mixture was stirred at 100° C. for 75 minutes. The mixture was cooled to room temperature. Thereto was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted with ethyl acetate twice again. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=2/1, followed by chloroform/methanol=92/8 to 3/1). The mixture was concentrated under reduced pressure, and the resulting residue was slurry-washed with a mixed solvent of n-heptane/ethanol (3/1) to give the titled compound (177 mg).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([C@@:4]1([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1ccc(F)cc1
Reactant: C=CC[C@]1(c2cccs2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CC[C@]1(c2cccs2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)O1
Yield: 72.9 %

Procedure:
Pd(PPh3)2Cl2 (100 mg) was added to the solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (1.0 g, 2.5 mmol), 4-fluorophenylboronic acid (420 mg, 3.0 mmol) in 1,4-dioxane. Cs2CO3 (5 mL) was slowly added. The mixture was heated to reflux for 2 h. The mixture was quenched with water and separated, extracted with EtOAc twice, dried over anhydrous Na2SO4 and concentrated to afford the residue, which was purified by TLC to give (R)-6-allyl-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (768 mg, 73%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][NH2:11])[CH:8]=1)([O-:3])=[O:2].CN1C(=O)CCC1.Cl[C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:29][O:28][C:22]1[CH:23]=[C:24]([O:26][CH3:27])[N:25]=[C:20]([NH:11][CH2:10][CH2:9][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]2)[N:21]=1
Reactant: NCCn1cc([N+](=O)[O-])cn1
Reactant: COc1cc(OC)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1cc(OC)nc(NCCn2cc([N+](=O)[O-])cn2)n1
Temperature: 150 °C

Procedure:
A microwave tube was charged with 2-(4-nitro-1H-pyrazol-1-yl)ethanamine (1.92 g, 5.52 mmol), NMP. (15 mL), 2-chloro-4,6-dimethoxypyrimidine (1.16 g, 6.62 mmol) and K2CO3 (4.19 g, 30.34 mmol). The resulting mixture was heated to 150° C. for 20 min in the microwave (no cooling). The reaction mixture was diluted with DCM and washed with water. The org. layer was separated and the aq. layer was extracted with DCM (2×) The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification was performed by FC (EtOAc/hept 6:4) to obtain 4,6-dimethoxy-N-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine. LC-MS conditions A: tR=0.33 min, [M+H]+=no ionization.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].N[C:11](N)=[O:12]>>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:9][C:11]1=[O:12]
Reactant: NC(N)=O
Reactant: CNc1ccccc1N
Product: Cn1c(=O)[nH]c2ccccc21
Temperature: 175 °C
Reaction time: 16 h
Yield: 26.5 %

Procedure:
A mixture of 24.4 grams (0.2 mole) of N-methyl-o-phenylenediamine and 14.4 grams (0.24 mole) of urea was prepared. The mixture was stirred for 16 hours in an oil bath maintained at 175° C. The reaction mixture then was cooled to about 80° C., 250 ml. of alcohol were added, and the mixture was refluxed for 20 minutes and then was filtered while hot. The filtrate was allowed to cool to room temperature and was refrigerated overnight. The crystals that formed were filtered, dried, and recrystallized from water to obtain 7.84 grams of 3-methyl-2-oxobenzimidazole, melting point 188°-189° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[S:65][CH:66]=[C:67]([C:69]([O:71][CH2:72][CH3:73])=[O:70])[N:68]=1>>[CH2:72]([O:71][C:69]([C:67]1[N:68]=[C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])[S:65][CH:66]=1)=[O:70])[CH3:73]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1csc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)n1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.25 g, 1 mmol), then reacted with ethyl 2-aminothiazole-4-carboxylate (Oakwood) (0.13 g, 0.78 mmol) to give rac-2-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-thiazole-4-carboxylic acid ethyl ester as a off white solid (Yield 0.1 g, 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1.[CH3:15][C@H:16]1[O:21][C@@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:22][C@H:20]1[O:21][C@@H:16]([CH3:15])[CH2:17][N:18]([C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=3[CH:8]=2)=[O:13])[CH2:19]1
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2oc(C(=O)N3C[C@@H](C)O[C@@H](C)C3)cc2c1

Procedure:
In a flask were mixed together the above prepared 5-methoxy-benzofuran-2-carboxylic acid (0.428 g, 2.23 mmol), cis-2,6-dimethylmorpholine (0.308 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (1.18 g, 1.2 eq.) and 2.4 eq. of N-ethyldiisopropylamine (0.915 mL) in 9 mL of abs. THF and allowed to react during one night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=7/3 generated 0.614 g of the title compound as colorless oil.
Reaction SMILES: [NH2:1][N:2]1[C:7]([NH2:8])=[CH:6][C:5]([NH2:9])=[N:4][C:3]1=[S:10].[CH:11](O)=O>>[NH2:9][C:5]1[N:4]=[C:3]([SH:10])[N:2]2[N:1]=[CH:11][N:8]=[C:7]2[CH:6]=1
Reactant: O=CO
Reactant: Nc1cc(N)n(N)c(=S)n1
Product: Nc1cc2ncnn2c(S)n1

Procedure:
A mixture of 1,4,6-triamino-2(1H)-pyrimidinethione (2.0 g) and 40 ml of formic acid was refluxed for seven hours. After concentrating under reduced pressure, 80 ml of water was added to the residue, the mixture was refluxed for one hour, and the crystals formed upon cooling were collected by filtration and washed with methanol, giving 1.6 g of the objective compound as faint yellow crystals.
Reaction SMILES: C1(C)C=CC=CC=1.FC(F)(F)S(O[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[CH:22]=2)[CH:17]=[N:16][CH:15]=1)(=O)=O.CC1(C)C(C)(C)OB([C:43]2[CH:58]=[CH:57][C:46]([O:47][CH2:48][CH2:49][O:50][CH:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[CH:45][CH:44]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[O:54]1[CH2:53][CH2:52][CH:51]([O:50][CH2:49][CH2:48][O:47][C:46]2[CH:57]=[CH:58][C:43]([C:17]3[C:18]4[C:23](=[CH:22][C:21]([C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])=[CH:20][CH:19]=4)[CH:14]=[CH:15][N:16]=3)=[CH:44][CH:45]=2)[CH2:56][CH2:55]1
Reactant: CC1(C)OB(c2ccc(OCCOC3CCOCC3)cc2)OC1(C)C
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(OS(=O)(=O)C(F)(F)F)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOC(=O)c1ccc2c(-c3ccc(OCCOC4CCOCC4)cc3)nccc2c1
Yield: 51.8 %

Procedure:
Into toluene (10 ml), 2-(trimethylsilyl)ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-6-carboxylate (500 mg, 1.2 mmol) was dissolved, to which 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethoxy}tetrahydro-2H-pyran (630 mg, 1.8 mmol) synthesized in Reference Example 2, 4,5-bis(diphenylphosphino)-9-dimethylxanthene (210 mg, 0.36 mmol), tris(dibenzylideneacetone)palladium (160 mg, 0.17 mmol), and potassium carbonate (500 mg, 3.6 mmol) were added. The resulting mixture was stirred at 100° C. for four hours, to which ethyl acetate was added. The resulting mixture was sequentially washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-50:50, V/V) to give the desired title compound (307 mg, yield 52%).
Reaction SMILES: C1C=CC([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[OH:16])=[O:8])=CC=1.C(O)[C@H]1[O:23][C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>>[OH:16][C:10]1[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=1[C:7]([OH:8])=[O:23]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: O=C(O)c1ccc(O)cc1O

Procedure:
The same methodology as described in Example 7 was repeated with 2,4-DHB in place of 3-HB, to produce the dose response curve for 2,4-DHB (FIG. 2). From FIG. 2 it can be seen that 2,4-DHB also enhances the sweetness of the sucrose solution but there is little difference between the 400 ppm solution (SEV 6.5%) and the 1000 ppm solution (SEV 6.7%). The maximum attainable sweetness would appear to be about 6.7% SEV (based on a 5% sucrose solution).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[CH3:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=3)=[O:29])=[C:3]([CH3:19])[CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1N
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Cc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Method H3 was used with 4-(4-amino-3-methylphenoxy)-3-nitropyridin-2-amine and 4-chloro-3-trifluoromethyl-phenyl isocyanate to afford the title compound (582 mg, 78%. 1H-NMR (δ, ppm, DMSO-d6): 2.25 (s, 3H, CH3), 5.95 (d, 1H, HPy,5, J=5.7 Hz), 6.96 (m, 2H, Harom), 7.02 (m, 1H, Harom), 7.12 (s, 2H, NH2,Py), 7.48-7.68 (m, 2H, Harom), 7.73 (d, 1H, Harom), 7.95 (d, 1H, HPy,6, J=5.7 Hz), 8.13 (m, 1H, Harom), 8.65 (s, 1H, NHurea1), 9.99 (s, 1H, NHurea3). LC-MS (m/z): 482 (M+H, 100).
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:3]1.[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[O:1]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:3]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCc3ccccc3C(O)C2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCc3ccccc3C(Oc3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a solution of 1-hydroxy-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine (10 g, 32 mmole), phenol (3.4 g, 36 mmole) and triphenylphosphine (9.5 g, 36 mmole) in benzene (300 ml), cooled with an ice bath, was slowly dropped a solution of diethyl azodicarboxylate (6.3 g, 36 mmole) in benzene (100 ml). After stirring twenty hours at ambient temperature, the reaction mixture was filtered to remove sym-dicarbethoxyhydrazine. The filtrate was concentrated to an oil which was dissolved in ether and cooled to precipitate the product and triphenylphosphine oxide. The desired product was crystallized from methanol to give a solid of 1-phenoxy-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine (6.8 g, 33%, m.p. 155°-156° C.).
Reaction SMILES: COC([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][C:7]1=[O:16])=O.[CH3:17][Si](I)(C)C>C(#N)C.C(OCC)(=O)C>[NH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]([CH3:17])[C:7]1=[O:16]
Reactant: COC(=O)NC1C(=O)NCc2ccccc21
Reactant: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1Cc2ccccc2C(N)C1=O

Procedure:
Step D—Removal of the Methoxyoxycarbonyl Group (MOC): To the 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one (3.4 mmoles) in 30 mL of acetonitrile was added 2 mole equivalents of trimethylsilyliodide (TMSI). The reaction mixture was heated to 50–80° C. for 3 hrs and then cooled and poured into a seperatory funnel. The reaction mixture was diluted with ethyl acetate and washed with 1 molar K2CO3 and then with 5% NaHSO3. The organic layer was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give the 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivative. Typical yields range from 50–87%.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([F:17])=[C:9]([CH:16]=1)[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14].[H-].[Na+].[CH3:22][O:23][CH2:24]Br.O>CN(C)C=O>[CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([F:17])=[C:9]([CH:16]=1)[CH2:10][N:11]([CH2:22][O:23][CH3:24])[C:12](=[O:15])[O:13][CH3:14]
Reactant: COCBr
Reactant: COC(=O)NCc1cc(C#CC(C)(C)C)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCN(Cc1cc(C#CC(C)(C)C)ccc1F)C(=O)OC
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
0.20 g of methyl N-[5-(3,3-dimethyl-1-butynyl)-2-fluorobenzyl]carbamate was dissolved in N,N-dimethylformamide (5 ml). To this solution, 0.10 g of sodium hydride (60 wt %) was added at room temperature, followed by stirring for 30 minutes. Then, 0.14 g of bromomethyl methyl ether was added at room temperature, followed by stirring for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.13 g of methyl N-[5-(3,3-dimethyl-1-butynyl)-2-fluorobenzyl]-N-methoxymethylcarbamate as a colorless viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][CH2:21][CH2:20]5)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].CCN(CC)CC.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C>C(Cl)Cl>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([C:39]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([N:12]4[CH2:13][CH2:14][C:15]5[N:16]=[C:8]([C:5]6[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=6)[S:9][C:10]=5[C:11]4=[O:26])=[CH:25][CH:24]=3)[CH2:20][CH2:21]2)=[O:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: O=C1c2sc(-c3ccc(Cl)cc3)nc2CCN1c1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCc3cc(N4CCc5nc(-c6ccc(Cl)cc6)sc5C4=O)ccc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-5-(2,3-dihydro-1H-indol-5-yl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (163 mg, 0.43 mmol) in CH2Cl2 (4.0 mL) and add (±)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (140 mg, 0.65 mmol), Et3N (0.09 mL, 0.64 mmol), and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (246 mg, 0.65 mmol). Stir the solution at room temperature for 2 h. Concentrate and purify by flash chromatography, using a 8% MeOH (2N NH3)/CHCl3 as eluent, to give the title compound (231 mg, 93%). 1H NMR (400 MHz, DMSO-d6): δ 8.10 (d, 1H, J=8.8 Hz), 8.05 (d, 2H, J=8.8 Hz), 7.62 (d, 2H, J=8.3 Hz), 7.29 (s, 1H), 7.19-7.15 (m, 1H), 4.22 (t, 2H, J=8.8 Hz), 4.07 (t, 2H, J=7.0 Hz), 3.54 (t, 1H, J=8.8 Hz), 3.47-3.36 (m, 3H), 3.29 (m, 1H), 3.26 (t, 2H, J=6.2 Hz), 3.18 (t, 2H, J=8.3 Hz), 2.16 (m, 1H), 2.01 (m, 1H), 1.41 (s, 9H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:10][C:11]([CH3:13])=O.O>C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:11](=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])([CH3:13])[CH3:10]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)C(C(=O)OC)=C(C)C
Reaction time: 24 h

Procedure:
A solution of 51 grams (0.39 mol) of dimethyl malonate, 30 grams of acetone, and 2.5 grams of zinc chloride in 50 mL of acetic anhydride was refluxed with stirring for 24 hours. The solution was poured into ice and water, then extracted with 200 mL of dichloromethane. The organic phase was washed 2×150 mL water, dried over sodium sulfate and concentrated to a brown oil. After two distillations the 41 gram fraction collected at 25°-34° C. (0.1 mm Hg) gave satisfactory analytical for dimethyl isopropylidenemalonate.
Reaction SMILES: [Cl-].C[Al+]C.[N+:5]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[CH:13]2)([O-:7])=[O:6].[C:17](Cl)(=[O:19])[CH3:18].[Cl-].[NH4+]>CCCCCC.ClCCl>[C:17]([C:13]1[C:12]2[C:16](=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=[CH:10][CH:11]=2)[NH:15][CH:14]=1)(=[O:19])[CH3:18]
Reactant: O=[N+]([O-])c1cccc2cc[nH]c12
Reactant: CC(=O)Cl
Agent: C[Al+]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=O)c1c[nH]c2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1.0M solution (11 ml) of dimethylaluminum chloride (11 mmol) in hexane was added to 50 ml of a solution of 1.2 g (7.5 mmol) of 7-nitro-1H-indole in dichloromethane at 0° C. in a nitrogen atmosphere, followed by the addition of 2.1 ml (29.5 mmol) of acetyl chloride at 0° C. The obtained mixture was stirred at room temperature for 4 hours, followed by the addition of a saturated aqueous solution of ammonium chloride. The precipitate thus formed was recovered by filtration and washed with hot ethanol sufficiently. The washings and the filtrate were combined and concentrated. Water was added to the residue and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and distilled in a vacuum to remove the solvent. The residue was purified by silica gel column chromatography to give 3-acetyl-7-nitro-1H-indole. This product was dissolved in 100 ml of methanol and hydrogenated in the presence of palladium-carbon at ordinary temperature under normal pressure. After the removal of the catalyst by filtration, the filtrate was concentrated to dryness to give 790 mg of the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Na+].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O-])(=[O:16])=[O:15])=[CH:10][CH:9]=1>O>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([Cl:2])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
PCl5 (0.44 mol, 89.2 g) was added to p-toluenesulfonic acid sodium salt (0.4 mmol, 77.6 g). After mixed completely, the mixture was heated to 80° C. in water bath and stirred for 2 h, then cooled to room temperature. The reaction was quenched by pouring onto 600 mL of water and ice. The mixture was filtered and gives the product as white solid. (69.8 g, 90%).