Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.OS([O-])(=O)=O.[K+]>C1COCC1>[CH2:31]([O:30][CH2:29][CH2:28][CH2:27][CH:5]1[CH2:4][NH:3][C:2](=[O:1])[CH2:7][C:6]1=[O:8])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCCCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CC(=O)C(CCCOCc2ccccc2)CN1
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
To a solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (3.84 g, 18 mmol) in anhydrous THF (100 mL), cooled at −20° C. under nitrogen atmosphere, 1M LiHMDS in THF (54 mL) was added dropwise. After 20 min under stirring, (3-bromo-propoxymethyl)-benzene (54 mmol) was added and the solution was stirred at −20° C. for 2 hours. The reaction mixture was poured into 5% aq. KHSO4 and extracted with DCM two times. The collected organic layers were concentrated to 500 mL and 50 mL of TFA were added. The resulting solution was stirred at room temperature for 1 hour. After evaporation, the residue was purified by column chromatography (hexane/EtOAc 1:2) affording 3.85 g of the title compound (14.7 mmol, 82%).
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: OB(O)c1ccccc1Br
Reactant: O=Cc1c[nH]c(Br)c1
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: [Na+]
Product: O=Cc1c[nH]c(-c2ccccc2Br)c1

Procedure:
By a similar operation as in Reference Example 148 and using 5-bromo-1H-pyrrole-3-carbaldehyde (870 mg), (2-bromophenyl)boronic acid (1.20 g), sodium carbonate (1.27 g) and tetrakis(triphenylphosphine)palladium (289 mg), the title compound was obtained as colorless crystals (yield 396 mg, 32%).
Reaction SMILES: [CH:1]1([CH:4]2[S:9][CH2:8][CH2:7][NH:6][CH2:5]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)=[CH:23][C:24]([C:28]#[N:29])=[N:25]2)=[CH:20][CH:19]=1>CC#N.CCOC(C)=O>[CH:1]1([CH:4]2[CH2:5][N:6]([CH2:17][C:18]3[CH:27]=[C:26]4[C:21]([C:22]([C:30]5[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=5)=[CH:23][C:24]([C:28]#[N:29])=[N:25]4)=[CH:20][CH:19]=3)[CH2:7][CH2:8][S:9]2)[CH2:3][CH2:2]1
Reactant: C1CSC(C2CC2)CN1
Reactant: Cn1cc(-c2cc(C#N)nc3cc(CBr)ccc23)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1cc(-c2cc(C#N)nc3cc(CN4CCSC(C5CC5)C4)ccc23)cn1
Temperature: 60 °C
Yield: 45.2 %

Procedure:
To a solution of crude 2-cyclopropylthiomorpholine (4-14, 100 mg, 0.698 mmol) in CH3CN (3 ml) was added K2CO3 (289 mg, 2.094 mmol) then 7-(bromomethyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile (251 mg, 0.768 mmol) all at once as solid. The resulting mixture was heated to 60° C. overnight. The mixture was cooled to rt, diluted with EtOAc, filtered through a pad of Celite washing with EtOAc, and concentrated. The crude product was subjected to silica gel chromatography (25 g, 0-100% EtOAc/hexanes, 10 minute gradient) to afford 7-((2-Cyclopropylthiomorpholino)methyl)-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carbonitrile (4-15, 123 mg, 45%) as a light orange foam. 1H NMR (399 MHz, CDCl3): δ 8.19 (d, J=8.7 Hz, 1 μl); 8.09 (s, 1 μl); 7.85 (s, 1 μl); 7.77 (s, 1H); 7.71 (d, J=8.8 Hz, 1H); 7.61 (s, 1H); 4.07 (s, 3H); 3.85-3.70 (m, 2 μl); 3.16 (dd, J=11.6, 2.7 Hz, 1H); 3.01 (d, J=11.6 Hz, 1H); 2.83 (ddd, J=13.4, 10.6, 2.7 Hz, 1H); 2.61-2.53 (m, 1H); 2.45-2.34 (m, 2H); 2.20-2.13 (m, 1H); 0.88-0.80 (m, 1H); 0.61-0.44 (m, 2H); 0.36-0.27 (m, 1H); 0.23-0.16 (m, 1H).
Reaction SMILES: [C:1](O)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][NH:9][C:10]([NH2:12])=[S:11].P(Cl)(Cl)(Cl)=O.Cl>O1CCOCC1.O>[NH2:12][C:10]1[S:11][C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[N:8][N:9]=1
Reactant: NNC(N)=S
Reactant: CC(C)(C)C(=O)O
Agent: Cl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1nnc(N)s1
Yield: 64.2 %

Procedure:
A three-liter reaction flask fitted with a power stirrer, heating mantle, dropping funnel, thermometer and water-cooled condenser was charged with 449 g (4.4 moles) of pivalic acid and 1500 ml of dioxane. To the stirred solution there was added 364 g (4.0 moles) of thiosemicarbazide. The dropping funnel was charged with 765 g (5.0 moles) of phosphorus oxychloride which was added to the well stirred solution in the reaction vessel. The reaction mixture was stirred and heated at 95°-100°. When the evolution of hydrogen chloride was complete, the mixture was cooled and the liquid phase was removed by decantation. Sufficient hot water was added to dissolve the pot residue. With ice-bath cooling and agitation, there was slowly added 450 ml of 50% aqueous sodium hydroxide. The mixture was cooled to 20° and the product was collected on a vacuum filter. The filter cake was washed with water and dried. There was obtained 404 g (64.2%) of 2-amino-5-tert-butyl-1,3,4-thiadiazole, m.p. 187°-88°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([OH:16])[CH2:13][C:14]#[N:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C1COCC1>O>[NH2:15][CH2:14][CH2:13][C@@H:12]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[CH:3]=1)[OH:16]
Reactant: N#CC[C@H](O)c1ccc(C(F)(F)F)c(F)c1
Solvent: C1CCOC1
Solvent: O
Product: NCC[C@H](O)c1ccc(C(F)(F)F)c(F)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of 282 (0.5 g, 2.1 mmol) and THF (10 mL) was added BH3—SMe2 (2.1 mL, 4.3 mmol) and the reaction was stirred at 65° C. for 8 h. The reaction was poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with EtOAc/MeOH/NH4OH (90/9/1) to afford 0.48 g (94%) of (S)-3-amino-1-(3-fluoro-4-(trifluoromethyl)phenyl)propan-1-ol (284).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH3:38][N:39](C)C(=O)C>C(OCC)(=O)C.O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:38]#[N:39])=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(C#N)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 120 °C
Reaction time: 8 h

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene (500 mg) obtained in Example 159-(1) was dissolved in N,N-dimethylacetamide (10 ml), and added thereto were zinc cyanide (98 mg), tris(dibenzylideneacetone)dipalladium(0) (77 mg), 1,1′-bis(diphenylphosphino)ferrocene (47 mg) and zinc power (14 mg). The mixture was heated under stirring at 120° C. overnight. The reaction solution was cooled, diluted with ethyl acetate and water, and the insoluble materials were filtered off. The organic layer of the filtrate was washed twice with water and successively washed with brine. After drying the same over sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-50:50) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-cyano-2-thienylmethyl)-4-methylbenzene (207 mg) as colorless crystals. APCI-Mass m/Z 561 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-cyano-2-thienylmethyl)-4-methylbenzene was treated in a manner similar to Example 106-(3) to give the desired 1-(β-D-glucopyranosyl)-3-(5-cyano-2-thienylmethyl)-4-methylbenzene as colorless powder. APCI-Mass m/Z 393 (M+NH4).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([OH:10])=O)[N:6]=1.P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.[NH2:32][CH:33]1[C:43](=[O:44])[N:35]2[C:36]([C:40]([OH:42])=[O:41])=[CH:37][CH2:38][S:39][C@H:34]12>O1CCCC1.CN(C)C=O.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([NH:32][CH:33]2[C:43](=[O:44])[N:35]3[C:36]([C:40]([OH:42])=[O:41])=[CH:37][CH2:38][S:39][C@H:34]23)=[O:10])[N:6]=1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: CCCCCCON=C(C(=O)O)c1csc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 24.3 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 3 g.), water (0.15 g.), phosphoryl chloride (3.8 g.), trimethylsilyl-acetamide (10.7 g.), N,N-dimethylformamide (1.0 g.), tetrahydrofuran (50 ml.) and 7-amino-3-cephem-4-carboxylic acid (2.0 g.) were treated in a similar manner to that of Example 18 to give 7-[2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.1 g.).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[CH:18][CH:19]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCCOC2CCCCO2)cc1)Oc1ccc(F)cc1
Yield: 96 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 2-(4-fluorophenoxy)-3-(4-hydroxyphenyl)propionate (2.75 g), which is the product of Reference example 37(b), 2-(2-bromoethyoxy)tetrahydropyran (2.08 g)and potassium carbonate (3.75 g) and the reaction mixture was treated to afford the desired compound (3.75 g) as a colorless oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[CH:8]=2)=[CH:5][CH:6]=1.S(OC)(O[CH3:24])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:24][O:18][C:14]1[CH:15]=[C:16]2[O:17][C:7]([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)=[CH:8][C:9](=[O:10])[C:11]2=[C:12]([OH:19])[CH:13]=1
Reactant: COS(=O)(=O)OC
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(O)c2c(=O)cc(-c3ccccc3)oc2c1

Procedure:
Prepared from chrysin by warming with one equivalent of dimethyl sulphate in DMF with fine ground K2CO3. Fine, light yellow needles, mp 175-180 ° C. (lit. 163° C.). 1H NMR δ (DMSO-d6) 3.87 (s,OCH3), 6.39 (d. J=1.7 Hz, H-6), 6.80 (d, J=1.7 Hz, H-8), 7.02 (s,H-3), 7.58 (dd, J=J'=7.8 Hz. H-3'/5'), 7.60 (tt, J≈7.8 Hz, H-4'), 8.09 (d,J=7.8 Hz, H-2'/6') 12.80 (s, C-5-OH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22](C2C=NC=CC=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][N:21]([CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NC(c2cccnc2)c2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(CCc2ccccc2)Cc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-2-phenethyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 75-76° C.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C@H:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)=[O:6].Cl>>[CH3:12][C:9]1([CH3:13])[O:8][C@@H:7]([C:5]([OH:6])=[O:4])[CH2:11][O:10]1
Reactant: COC(=O)[C@H]1COC(C)(C)O1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC1(C)OC[C@H](C(=O)O)O1
Reaction time: 3 h
Yield: 79 %

Procedure:
To a 2 N aqueous solution of potassium hydroxide was added (R)-(+)-2,2-dimethyl-1,3-dioxolan-4-carboxylic acid methyl ester (1.00 g, 6.24 mmol), followed by stirring under ice cooling conditions for 3 hours. After neutralization with hydrochloric acid, the solution was salted out and extracted with ethyl acetate (50 ml) to yield (R)-(+)-2,2-dimethyl-1,3-dioxolan-4-carboxylic acid as colorless amorphous powders (0.72 g). To a solution of the compound obtained in Reference Example 29 (0.572 g, 1.0 mmol) in dichloromethane (5 ml) were added diisopropylethylamine (1.04 g, 8 mmol) and the (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid obtained (0.292 g, 2 mmol), followed by stirring under ice cooling conditions. To this solution was added benzotriazol-1-yloxytrisdimethylaminophosphonium hexafluorophosphate (BOP reagent) (0.885 g, 2 mmol). After stirring under ice cooling conditions for 1 hour, the solution was further stirred at room temperature for 4 days. The reaction mixture was concentrated to dryness under reduced pressure, and then the obtained residue was partitioned between water (50 ml) andchloroform(50 ml). The water layer was again extracted with chloroform (10 ml). The combined extracts were washed with saline, and dried (MgSO4), the solvent was distilled off under reduced pressure. The obtained residue was chromatographed on silica gel to yield colorless amorphous powders (0.5 g), which was then dissolved in trifluoroacetic acid (10 ml) and stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure and treated with alkali, after which it was partitioned between chloroform (50 ml) and water (50 ml), and then the water layer was again extracted with chloroform (10 ml). The combined extracts were washed with saline, and dried (MgSO4), the solvent was distilled off under reduced pressure. The obtained residue was chromatographed on silica gel to yield 0.5 g of colorless amorphous powders (76%).
Reaction SMILES: [C:1]1([C:7]2[C:12]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][O:17][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[C:1]1([C:7]2[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][O:17][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2cccc(-c3ccccc3)c2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(-c2cccc3c2CNCCO3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A mixture of tert-butyl 6-phenyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (90.0 mg, 0.265 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (68.5 mg, 98.7%) as a solid.
Reaction SMILES: OC(C)(C)[C:3]#[C:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][CH3:14])[CH:8]=1.[OH-].[K+]>C1C=CC=CC=1>[CH3:14][NH:13][C:9]1[CH:8]=[C:7]([C:6]#[C:5][C:4]#[CH:3])[CH:12]=[CH:11][CH:10]=1
Reactant: CNc1cccc(C#CC#CC(C)(C)O)c1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: C#CC#Cc1cccc(NC)c1
Yield: 42.9 %

Procedure:
1600 mg of the thus-obtained diacetylene compound were then dissolved in 300 ml of benzene, and 450 mg of potassium hydroxide were then added to the reaction mixture, followed by reflux under heating for 1 hour. After filtration, the solvent was evaporated, and the residue was then purified by silica-gel column chromatography using benzene as an eluent to obtain 500 mg of 1-[3-(N-methylamino)phenyl]-1,3-butadiyne.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(#N)C.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(S(C)(=O)=O)cc1)=C2Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc2c(Br)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reaction time: 1 h

Procedure:
Combine 1-bromo-2-(4-methanesulfonylphenyl)-3,4-dihydro-6-methoxynaphthalene and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 1.8 equiv.) in 10 volumes acetonitrile and 5 volumes of THF. Under nitrogen atmosphere, heat reaction contents to 73-75° C. Monitor reaction progress by GC analysis until reaction, completion. Additional DDQ (0.2-0.3 equiv.) may be required for reaction completion. Cool contents to ambient temperature and add 10 volumes 1 N sodium hydroxide. Stir for approximately 1 hour and filter. Rinse filter cake with 2 volumes water, 3×5 volumes 50% acetonitrile/water and finally 3 volumes methanol. Vacuum dry the filter cake at 65° C. to give the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH:13]=[N:12]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[NH2:53][CH2:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:63](=[O:74])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=2[C:70]([F:73])([F:72])[F:71])[CH2:59][CH2:58]1)=[O:56]>CN(C=O)C.O>[CH3:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([NH:53][CH2:54][C:55](=[O:56])[N:57]3[CH2:58][CH2:59][N:60]([C:63](=[O:74])[C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=4[C:70]([F:71])([F:73])[F:72])[CH2:61][CH2:62]3)=[O:22])=[CH:23][CH:24]=2)[CH:13]=[N:12]1
Reactant: Cn1cc(-c2ccc(C(=O)O)cc2)cn1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc(C(=O)NCC(=O)N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 52.7 %

Procedure:
DIPEA (76.2 mg, 0.09 mL, 0.59 mmol) was added to a stirred solution of 4-(1-methyl-1H-pyrazol-4-yl)-benzoic acid (40 mg, 0.19 mmol) in DMF (1 mL). HOBT (32 mg, 0.23 mmol) and EDCI (46 mg, 0.23 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone trifluoroacetic acid salt (102 mg, 0.23 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 50 mg (50.5% yield) of 4-(1-methyl-1H-pyrazol-4-yl)-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 90.78%. 1H NMR (DMSO-d6): δ 8.6-8.5 (bt, 1H), 8.3-8.2 (s, 1H), 8.0-7.8 (s, 1H), 7.9-7.84 (m, 3H), 7.8-7.74 (m, 1H), 7.74-7.6 (m, 3H), 7.6-7.5 (m, 1H), 4.2-4.1 (m, 2H), 3.9-3.88 (s, 3H), 3.84-3.68 (m, 2H), 3.68-3.54 (m, 2H), 3.54-3.4 (m, 2H), 3.22-3.0 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][OH:16])[CH3:12].[H-].[Na+].O>CN(C=O)C>[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][O:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: CCN(CC)CCO
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To the solution of 8.0 g (51 mMol) of 1-chloro-4-nitrobenzene and 6.0 g (6.8 mL; 51 mMol) of 2-diethylamino-ethanol in 50 mL of DMF at 0° C. is added 2.7 g of NaH portionwise over 2 h. After stirring another hour at rt, the reaction mixture is poured onto 300 mL of water and stirred. After filtering off some crystalline product, the aqeous layers are extracted with ethyl acetate. The combined organic layers are dried and evaporated to obtain diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine. Title compound: ES-MS: 239 [M+H]+; single peak at tR=5.1 min (System 2).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(OC1C=C(C(=C=O)C(O)=O)C=CC=1OCC)C>>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:20][CH:21]([CH3:22])[CH3:23])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(=O)NC(=CC(C)C)c2ccccc2N2CCCCC2)cc1OCC
Agent: CCOc1ccc(C(=C=O)C(=O)O)cc1OCC
Product: CCOC(=O)c1ccc(CC(=O)NC(CC(C)C)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared from ethyl 2ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-buten-1-yl}-aminocarbonylmethyl]-benzoate, melting point 125°-126° C., which in turn was prepared from (2-piperidino-phenyl)-isobutyl-ketimine and 3-ethoxy-4-ethoxy-carbonyl-phenyl-acetic acid analogous to Example 1.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](O)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].B.CC(C)=O.O>O1CCCC1>[CH2:1]([O:17][CH2:18][CH2:19][OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCOCCO
Yield: 92.6 %

Procedure:
A solution of 80 g of (hexadecyloxy) acetic acid in 350 ml of tetrahydrofuran was stirred at 0° C. while 798.71 ml of 1M borane in tetrahydrofuran was added dropwise over one hour. When addition was complete the mixture was stirred 2 hours than 50 ml of acetone was added followed by 60 ml of water dropwise. The tetrahydrofuran was allowed to evaporate overnight, then the residue was mixed with water and chloroform and heated to dissolve the solid. The organic layer was separated, dried and the solvent removed. The residue was recrystallized from cold methanol, giving 70.6 g of the desired compound as a white solid, mp 42°-44° C.