Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.[H-].[Na+]>CN(C)C=O>[ClH:1].[N:20]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3ccccc3c(-n3ccnc3)n2)cc1
Product: Cl
Temperature: 80 °C
Reaction time: 6 h

Procedure:
1-Chloro-3-(4-methoxyphenyl)isoquinoline (405 mg) and imidazole (204 mg) were dissolved in N,N-dimethylformamide (5 ml), followed by the addition of 60% sodium hydride (60 mg), and the resulting mixture was stirred at 80° C. for 6 hr. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), and then the resulting product was converted into a hydrochloride in a conventional manner, to give the hydrochloride of the title compound as a pale yellow amorphous (255 mg, yield; 53%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([NH:16][NH2:17])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([C:28](=O)[CH3:29])[CH:27]=1>CO.C(O)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26](/[C:28](=[N:17]/[NH:16][C:14](=[O:15])[C:13]2[CH:18]=[CH:19][CH:20]=[C:11]([S:8]([N:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]3)(=[O:10])=[O:9])[CH:12]=2)/[CH3:29])[CH:27]=1
Reactant: CC1CCN(S(=O)(=O)c2cccc(C(=O)NN)c2)CC1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCC(C)CC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 13.6 %

Procedure:
3-((4-methylpiperidin-1-yl)sulfonyl)benzohydrazide (70 mg, 0.235 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (40.2 mg, 0.235 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-((4-methylpiperidin-1-yl)sulfonyl)benzohydrazide (15 mg, 0.032 mmol, 13.60% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.11 (m, 2H), 7.81 (m, 1H), 7.59 (m, 1H), 7.39 (m, 1H), 7.19 (m, 1H), 6.89 (m, 1H), 3.69 (m, 2H), 2.41 (m, 2H), 2.24 (m, 2H), 1.63 (m, 2H), 1.24 (m, 4H), 0.87 (d, 3H, J=4.4 Hz). Mass [M+H]+:450.2
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7](C=O)[CH2:6][C:5]2([CH3:15])[CH3:14].O1[CH2:20][CH2:19][CH2:18]C1.C([Mg]Br)C.C(OCC)(=O)C>C(OCC)C.CCCCCC>[CH:18]1([CH:8]2[C:9]3[C:4](=[CH:3][C:2]([OH:1])=[CH:11][CH:10]=3)[C:5]([CH3:14])([CH3:15])[CH2:6][NH:7]2)[CH2:19][CH2:20]1
Reactant: C1CCOC1
Reactant: CC1(C)CN(C=O)Cc2ccc(O)cc21
Agent: CC[Mg]Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)CNC(C2CC2)c2ccc(O)cc21
Temperature: 55 °C
Yield: 63 %

Procedure:
A stirred, cooled (0° C.)solution of 6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde (Intermediate 20, 2.3 g, 11.21 mmol) anhydrous tetrahydrofuran (40 mL) under argon was treated with titanium tetra-iso-propoxide (8.28 mL, 28 mmol) followed by 3M solution of ethyl magnesium bromide in diethyl ether (18.7 mL) and the reaction mixture was then heated at 55° C. overnight. It was then cooled in an ice-bath, quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a yellow oily solid. Flash column chromatography over silica gel (230-400 mesh) using 10-20% ethyl acetate in hexane as the eluent afforded the title compound as a pale yellow solid (1.55 g, 63%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:14]2[CH:21]=[CH:20][NH:19][C:15]=2[N:16]=[CH:17][N:18]=1.[OH-].[Na+]>CC(C)=O>[Cl:12][C:13]1[C:14]2[CH:21]=[CH:20][N:19]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 162.1 %

Procedure:
To a clean, dry, nitrogen-purged reactor were charged acetone (87.5 ml), p-toluenesulfonyl chloride (17.1 g, 0.09 mol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (25.0 g, 0.16 mol). The reactor was cooled to between −5.0 to 5.0° C. and 2.5 M sodium hydroxide (78.1 ml) was added at a rate to maintain the temperature below 5.0° C. The reactor was warmed to between 20-30° C. and stirred for a minimum of 5 hours. The resulting solids were isolated by filtration and washed with acetone/water (1:1, 25 ml each). After drying for a minimum of 12 hours under vacuum at 40-50° C. with slight nitrogen bleed, 44.9 g (90.1%) of the title compound were isolated.
Reaction SMILES: CCN(C(C)C)C(C)C.[ClH:10].Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15][CH2:14]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:36](O)=[O:37])=[CH:31][CH:30]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[ClH:28].[ClH:10].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][N:40]2[CH2:41][CH2:42][CH2:43][CH2:44]2)[C:36]([N:25]2[CH2:26][CH2:27][N:22]([C:20]3[C:21]4[C@H:13]([CH3:12])[CH2:14][CH2:15][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:23][CH2:24]2)=[O:37])=[CH:31][CH:30]=1
Reactant: O=C(O)C(CN1CCCC1)c1ccc(Cl)cc1
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C(CN4CCCC4)c4ccc(Cl)cc4)CC3)c21
Reaction time: 120 h
Yield: 27.8 %

Procedure:
DIPEA (44.4 mg, 0.343 mmol) was added to a suspension of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (20 mg, 0.69 mmol), 2-(4-chlorophenyl)-3-(pyrrolidin-1-yl)propanoic acid (59.8 mg, 0.082 mmol), and O—(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (31.3 mg, 0.082 mmol) in CH2Cl2 (5.0 mL) at room temperature. The resulting mixture was stirred for 5 days, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous. NH4Cl. The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g), and eluted by a mixture of MeOH and CH2Cl2 (3:97 to 5:95) to give 2-(4-chlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(pyrrolidin-1-yl)propan-1-one dihydrochloride (6 mg, 17%) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[O:11]2)[CH2:7][CH2:6]1)=[O:4].[C:22](Cl)(=[O:25])[CH2:23][CH3:24].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([C:22](=[O:25])[CH2:23][CH3:24])[CH:18]=[CH:19][C:12]=3[O:11]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CCC(=O)Cl
Reactant: O=C(N1CCC2(CCc3ccccc3O2)CC1)C(F)(F)F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC(=O)c1ccc2c(c1)CCC1(CCN(C(=O)C(F)(F)F)CC1)O2
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
A mixture of 1′-trifluoroacetyl-spiro[3,4-dihydrobenzopyran-2,4′-piperidine] (1.49 g, 4.98 mmol) and propanoyl chloride (0.4 mL, 5 mmol) in methylene chloride (13 mL) was cooled at 10° C. Tin tetrachloride (1M solution in methylene chloride) (0.76 mL, 6.5 mmol) was added at 10° C. and stirred at 10° C. for 20 min then quenched with aqueous 2N HCl at 0° C. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude product. The crude product was purified by ISCO (80 g column) chromatography using 17 to 35% EtOAc in hexane to produce 1′-trifluoroacetyl-6-(propanoyl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine] (1.42 g, 81%),
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CN(C)C(N(C)C)=N>CS(C)=O.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:13]=[C:12]([O:21][CH3:22])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:18])[NH:17][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH2:28][CH2:29]3)[N:7]=1)=[N:9]2
Reactant: COCCN1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Agent: CN(C)C(=N)N(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCN1CCN(c2cccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)n2)CC1
Temperature: 80 °C
Yield: 49.9 %

Procedure:
A mixture of 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.100 g, 0.33 mmol), 1-(2-methoxyethyl)piperazine (0.072 g, 0.49 mmol) and 1,1,3,3-tetramethylguanidine (0.096 g, 0.83 mmol) in dry DMSO (2 mL) was heated at 80° C. for 17 h. After that time the reaction mixture was cooled to rt and diluted with ethyl acetate (30 mL). The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give 5,7-dimethoxy-2-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one (0.070 g, 49%) as a yellow solid: mp 99-101° C.; 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 7.85 (d, J=7.42 Hz, 1H), 7.61-7.71 (m, 1H), 6.77-6.87 (m, 2H), 6.48 (d, J=1.95 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.64-3.71 (m, 4H), 3.59 (t, J=5.47 Hz, 2H), 3.40 (s, 3H), 2.61-2.71 (m, 6H); ESI MS m/z 426 [M+H]+.
Reaction SMILES: [O:1]([C@H:13]1[C@H:19]([OH:20])[C@@H:18]([CH2:21][OH:22])[O:17][CH:15]([OH:16])[C@@H:14]1[NH2:23])[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.[O:24]([C@H:36]1[C@@H:42]([OH:43])[C@@H:41]([CH2:44][OH:45])[O:40][CH:38]([OH:39])[C@@H:37]1[NH2:46])[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O>>[OH:16][CH:15]1[O:17][C@H:18]([CH2:21][OH:22])[C@@H:19]([OH:20])[C@H:13]([OH:1])[C@H:14]1[NH2:23].[OH:39][CH:38]1[O:40][C@H:41]([CH2:44][OH:45])[C@H:42]([OH:43])[C@H:36]([OH:24])[C@H:37]1[NH2:46]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O

Procedure:
Example 3-Synthesis of Galβ1-3GlcNH2 βSEt and Galβ1-3GalNH2 βSEt. See example 1, similar conditions and enzyme may be used, but instead GlcNH2 βSEt, or GalNH2 βSEt to obtain the latter product, is used as the acceptor. Here, extraction is less favorable for isolation, and instead ion-exchanger as above may be used followed by e.g. precipitation or a second chromatographic step.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19].CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=[O:40].CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C(O)=O.CS(C)=O>CO>[CH3:1][C:2]1=[CH:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])/[C:3]/1=[CH:10]/[CH:11]=[C:12](/[CH:13]=[CH:14]/[CH:15]=[C:16](/[CH:17]([OH:40])[CH2:18][OH:19])\[CH3:20])\[CH3:21]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Agent: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Solvent: CO
Solvent: CS(C)=O
Product: CC1=CCCC(C)(C)/C1=C/C=C(C)/C=C/C=C(\C)C(O)CO

Procedure:
All-trans retinol, all-trans retinal and all-trans retinoic acid were purchased from Sigma Chemical Co. (St. Louis, Mo.). The retinoids were dissolved at a concentration of 3×10-2M in methanol or DMSO with 10-4M butylated hydroxytoluene (Sigma Chemical Co.) added and stored in the dark at -20° C. in a nitrogen atmosphere. Immediately before use, the stock solutions were diluted in serum-free medium. 14-Hydroxy-retro-retinol (14HRR) was isolated from the pellets of HeLa cells fed with retinol by using a series of reversed-phase HPLC columns as described (33). 14HRR was pure according to the retention time on an analytical C18 reversed-phase column and the typical UV absorption spectrum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:15][CH2:14]1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]([S:19]([N:16]1[CH2:17][CH2:18][CH:13]([C:5]2[C:4]3[C:8](=[C:9]([C:11]#[N:12])[CH:10]=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=4)[CH:3]=3)[NH:7][N:6]=2)[CH2:14][CH2:15]1)(=[O:21])=[O:20])[CH3:23]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(-c4ccc(F)cc4)cc23)CC1

Procedure:
Following the general procedure of Example 65, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carbonitrile (Intermediate 10) (50 mg, 0.102 mmols), 4-fluorophenyl boronic acid (42 mg, 0.306 mmols), potassium carbonate (84 mg, 0.612 mmol), and Pd(PPh3)4 (10 mg) in dioxane/water (6/1, 3.5 mL) were reacted to give the crude title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=[C:20]3[CH3:30])=[C:15](C)[CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:32][C:33]1[CH:40]=[C:39]([OH:41])[CH:38]=[CH:37][C:34]=1[CH:35]=O>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=[C:20]3/[CH:30]=[CH:35]/[C:34]3[CH:37]=[CH:38][C:39]([OH:41])=[CH:40][C:33]=3[OH:32])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=Cc1ccc(O)cc1O
Reactant: Cc1cc(C#Cc2ccc(C(C)(C)C)cc2)ccc1-n1c(C)nc2ccccc2c1=O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C#Cc2ccc(-n3c(/C=C/c4ccc(O)cc4O)nc4ccccc4c3=O)cc2)cc1
Reaction time: 8 h

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with 1-tert-butyl-4-ethynylbenzene (25b, 158 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 4-((4-tert-butylphenyl)ethynyl)-2-methyl benzene amine (26b) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 4-((4-tert-butylphenyl)ethynyl)-2-methylbenzenamine (26b, 263 mg, 1 mmol) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h After completion of the reaction as indicated by TLC. then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 3-(4-((4-tert-butylphenyl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29b). Reaction of 3-(4-((4-tert-butylphenyl)ethynyl)-2-methylphenyl)-2-methyl quinazolin-4(3H)-one (29b, 406 mg, 1 mmol) with 2,4-dihydroxybenzaldehyde (30d, 138 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (5d) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [O:1]=[C:2]1[C:15]2N([C:7](=[O:22])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)CCN1.C(N(CC)CC)C.CS(C)=[O:32]>>[O:32]=[C:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:15]([CH:2]=[O:1])[O:22]1
Reactant: CS(C)=O
Reactant: O=C1NCCn2c1c(-c1ccccc1)c1ccccc1c2=O
Solvent: CCN(CC)CC
Product: O=Cc1oc(=O)c2ccccc2c1-c1ccccc1

Procedure:
The compound obtained in Process 1 (2.5 g) was oxidized with SO3 -pyridine complex in DMSO in the presence of triethylarnine to yield 1-oxo-4-phenyl-1H-2-benzopyran-3-carboxaldehyde as colorless crystals (2.38 g).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[N:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[NH2:37].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:22])([F:21])[F:23])[C:12]2=[O:24])[C:8]([NH:37][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][N:31]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cnccn1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cnccn1)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26.6 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 160 mg, 0.47 mmol) in methylene chloride (10 mL) and N,N-dimethylformamide (1 drop) cooled to 0° C. was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 281 μL, 0.56 mmol) and stirred at 0° C. for 15 min. After this time, the reaction mixture was warmed to room temperature and then stirred for another 30 min. After this time, the reaction mixture was then concentrated in vacuo to ˜1 mL volume and an additional amount of methylene chloride (3 mL) was added. One half of this solution of prepared acid chloride (2 mL, 0.23 mmol) was added dropwise to a separate reaction flask containing a mixture of pyrazin-2-ylamine (33 mg, 0.35 mmol) and 2,6-lutidine (52 μL, 0.47 mmol) in methylene chloride (5 mL) cooled to 0° C. The resulting reaction mixture was then allowed to warm to room temperature and stirred for 16 h. After such time, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then extracted with methylene chloride (3×10 mL). The organic layers were then washed with a 1N aqueous hydrochloric acid solution (10 mL), dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate concentrated in vacuo. The crude material was purified via automated flash chromatography (12 g silica gel column, 25-75% ethyl acetate/hexanes and then a 4 g silica gel column, 40-60% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide (39 mg, 40%) as a white foam: [α]28D=−65.0° (c=0.10, methylene chloride); HR-ES(+) m/e calcd for C21H21N4O2F3 [M+H]+ 419.1690, observed 416.1688; 1H NMR (300 MHz, DMSO-d6) δ ppm 11.32 (s, 1H), 9.26 (s, 1H), 8.34-8.49 (m, 2H), 8.02 (t, J=8.45 Hz, 2H), 7.67-7.84 (m, 1H), 5.23 (dd, J=4.98, 10.41 Hz, 1H), 5.06 (d, J=18.41 Hz, 1H), 4.67-4.85 (m, 1H), 1.02-2.21 (m, 11H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11]([CH3:13])=[N:12][C:8]=2[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:34][Si:35]([CH3:43])([CH3:42])[CH2:36][CH2:37][S:38](Cl)(=[O:40])=[O:39]>C(#N)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]([S:38]([CH2:37][CH2:36][Si:35]([CH3:43])([CH3:42])[CH3:34])(=[O:40])=[O:39])[C:11]([CH3:13])=[N:12][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]c(C)nc2c1)NC(=O)OCc1ccccc1
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](Cc1ccc2c(c1)nc(C)n2S(=O)(=O)CC[Si](C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (R)-2-benzyloxycarbonylamino-3-(2-methyl-1H-benzoimidazol-5-yl)-propionic acid methyl ester (533 mg, 1.96 mmol), and sodium carbonate in acetonitrile (20 mL) was added neat 2-trimethylsilanyl-ethanesulfonyl chloride all at once. The mixture was stirred at room temperature overnight. Solvents were removed and the residue was purified by chromatography on silica gel using ethyl acetate/hexanes (1:2) as eluent to afford the title compound as a waxy solid (1:1 mixture of N1 and N3 isomers, 66%). 1H-NMR (CDCl3, 500 MHz) δ 7.68 (d, J=8.5 hz, 0.5H), 7.55 (d, J=8.5 Hz, 0.5H), 7.53 (s, 0.5H), 7.41 (s, 0.5H), 7.34–7.29 (m, 5H), 7.06–7.04 (m, 1H), 5.22 (d, J=8.0 Hz, 0.5H), 5.17 (d, J=7.5 Hz, 0.5H), 5.11–5.07 (m, 2H), 4.72–4.69 (m, 1H), 3.75 (s, 1.5H), 3.72 (s, 1.5H), 3.24–3.17 (m, 2H), 2.79 (s, 3H), 0.92–0.83 (m, 2H), −0.02 (s, 4.5H), −0.05 (s, 4.5H). Mass spec.: 532.26 (MH)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[O:7])#[N:2].[ClH:12].[H][H]>[Pt].O>[Cl-:12].[CH:6]([N:5]([CH2:4][CH2:3][CH2:1][NH3+:2])[CH2:8][CH2:9][CH2:10][OH:11])=[O:7]
Reactant: [H][H]
Reactant: Cl
Reactant: N#CCCN(C=O)CCCO
Agent: [Pt]
Solvent: O
Product: [Cl-]
Product: [NH3+]CCCN(C=O)CCCO

Procedure:
A solution of 15.6 g. (100 mmoles) of 3-[N-(2-cyanoethyl)-N-formylamino]-propanol in 225 ml. of water is treated with 100 ml. of 1 N hydrochloric acid and reduced over 3.8 g. of platinum at room temperature and 40 psi of hydrogen. The reaction mixture is filtered and concentrated under reduced pressure yielding 3-[N'-formyl-N'-(3-hydroxypropyl)amino]-1-propanaminium chloride.